Compounds and compositions as protein kinase inhibitors

ABSTRACT

The invention provides a novel class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly diseases or disorders that involve abnormal activation of the Abl, BCR-Abl, PDGF-R, trkB, c-SRC, BMX, FGFR3, b-RAF, ΣΓK, Tιε2, Λχκ, θNK2α2, MKK4, c-RAF, MKK6, SAPK2α and SAPK2β kinases.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is the National Stage of Application No.PCT/US2005020371, filed on Jun. 9, 2005, which claims benefit under 35U.S.C. 119(e) of U.S. Provisional Application No. 60/578,491 filed Jun.10, 2004. The contents of both are incorporated herein by reference intheir entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention provides a novel class of compounds, pharmaceuticalcompositions comprising such compounds and methods of using suchcompounds to treat or prevent diseases or disorders associated withabnormal or deregulated kinase activity, particularly diseases ordisorders that involve abnormal activation of the Abl, BCR-Abl, PDGF-R,trkB, c-SRC, BMX, FGFR3, b-RAF, SGK, Tie2, Lck, JNK2α2, MKK4, c-RAF,MKK6, SAPK2α and SAPK2β kinases.

2. Background

The protein kinases represent a large family of proteins, which play acentral role in the regulation of a wide variety of cellular processesand maintaining control over cellular function. A partial, non-limiting,list of these kinases include: receptor tyrosine kinases such asplatelet-derived growth factor receptor kinase (PDGF-R), the nervegrowth factor receptor, trkB, and the fibroblast growth factor receptor,FGFR3, B-RAF; non-receptor tyrosine kinases such Abl and the fusionkinase BCR-Abl, Lck, Bmx and c-src; and serine/threonine kinases such asc-RAF, sgk, MAP kinases (e.g., MKK4, MKK6, etc.) and SAPK2α and SAPK2β.Aberrant kinase activity has been observed in many disease statesincluding benign and malignant proliferative disorders as well asdiseases resulting from inappropriate activation of the immune andnervous systems.

The novel compounds of this invention inhibit the activity of one ormore protein kinases and are, therefore, expected to be useful in thetreatment of kinase-associated diseases.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides compounds of Formula I:

in which:

m and n are independently selected from 0, 1 and 2;

R₁ is selected from —XNR₅R₆, —XOR₅, —XC(O)R₅, —XR₅ and —XS(O)₀₋₂R₅;wherein X is a bond or C₁₋₄alkylene optionally substituted by 1 to 2C₁₋₆alkyl radicals; R₅, is selected from hydrogen, C₁₋₆alkyl,C₆₋₁₀aryl-C₀₋₄alkyl, C₅₋₁₀heteroaryl-C₀₋₄alkyl, C₃₋₁₀cycloalkyl-C₀₋₄alkyl and C₃₋₁₀heterocycloalkyl-C₀₋₄alkyl; and R₆ isselected from hydrogen and C₁₋₆alkyl; or R₅ and R₆ together with thenitrogen to which R₅ and R₆ are both attached form heteroaryl orheterocycloalkyl;

wherein any aryl, heteroaryl, cycloalkyl and heterocycloalkyl of R₅ orthe combination of R₅ and R₆ can be optionally substituted with 1 to 3radicals independently selected from halo, nitro, cyano, hydroxy,C₁₋₆alkyl, C₁₋₆alkoxy, halo-substituted-alkyl, halo-substituted-alkoxy,—XNR₇R₈, —XOR₇, —XNR₇S(O)₂R₈, —XNR₇S(O)R₈, —XNR₇SR₈, —XC(O)NR₇R₈,—XC(O)NR₇XNR₇R₈, —XNR₇C(O)NR₇R₈, —XNR₇XNR₇R₈, —XNR₇XOR₇,—XNR₇C(═NR₇)NR₇R₈, —XS(O)₂R₉, —XNR₇C(O)R₈, —XNR₇C(O)R₉, —-XR₉,—XC(O)OR₈, —XS(O)₂NR₇R₈, —XS(O)NR₇R₈ and —XSNR₇R₈; wherein X is a bondor C₁₋₄alkylene; R₇ and R₈ are independently selected from the groupconsisting of hydrogen and C₁₋₄alkyl; and R₉ is selected fromC₃₋₁₀heterocycloalkyl and C₅₋₁₀heteroaryl; wherein said heterocycloalkylor heteroaryl of R₉ is optionally substituted with a radical selectedfrom the group consisting of C₁₋₄alkyl, —XNR₇XNR₇R₇, XNR₇XOR₇ and —XOR₇;

R₂ and R₄ are independently selected from halo, hydroxy, C₁₋₄alkyl,C₁₋₄alkoxy, halo-substituted-C₁₋₄alkyl and halo-substituted-C₁₋₄alkoxy;

R₃ is selected from —NR₁₀R₁₁, —NR₁₀C(O)R₁₁, —NR₁₀S(O)₀₋₂R₁₁, and—NR₁₀C(O)NR₁₀R₁₁; wherein R₁₀ is selected from hydrogen and C₁₋₆alkyl;R₁₁ is selected from C₆₋₁₀aryl, C₅₋₁₀heteroaryl, C₃₋₁₀cycloalkyl andC₃₋₁₀heterocycloalkyl; wherein any aryl, heteroaryl, cycloalkyl orheterocycloalkyl of R₁₁, is optionally substituted by 1 to 3 radicalsselected from halo, nitro, cyano, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-alkyl, halo-substituted-alkoxy, —NR₁₂C(O)R₁₃,—NR₁₂C(O)NR₁₂R₁₃, —C(O)NR₁₂R₁₃, —NR₁₂S(O)₀₋₂R₁₃ and —S(O)₀₋₂NR₁₂R₁₃;wherein R₁₂ is selected from hydrogen and C₁₋₆alkyl; R₁₃ is selectedfrom C₆₋₁₀aryl, C₅₋₁₀heteroaryl, C₃₋₁₀cycloalkyl andC₃₋₁₀heterocycloalkyl; wherein any aryl, heteroaryl, cycloalkyl orheterocycloalkyl of R₁₃ is optionally substituted with 1 to 3 radicalsindependently selected from halo, C₁₋₆alkyl, halo-substituted-C₁₋₆alkyl,C₁₋₆alkoxy, halo-substituted-C₁₋₆alkoxy, —XNR₇R₈, C₆₋₁₀aryl-C₀₋₄alkyl,C₅₋₁₀heteroaryl-C₀₋₄alkyl, C₃₋₁₀ cycloalkyl-C₀₋₄alkyl,C₃₋₁₀heterocycloalkyl-C₀₋₄alkoxy and C₃₋₁₀heterocycloalkyl-C₀₋₄alkyl;wherein X, R₇ and R₈ are as described above and wherein any aryl,heteroaryl, cycloalkyl or heterocycloalkyl substituent of R₁₃ is furtheroptionally substituted by 1 to 3 radicals independently selected fromhalo, C₁₋₆alkyl, halo-substituted-C₁₋₆alkyl,hydroxy-substituted-C₁₋₆alkyl, C₁₋₆alkoxy, C₃₋₁₀heterocycloalkyl andhalo-substituted-C₁₋₆alkoxy; and the N-oxide derivatives, prodrugderivatives, protected derivatives, individual isomers and mixture ofisomers thereof, and the pharmaceutically acceptable salts and solvates(e.g. hydrates) of such compounds.

In a second aspect, the present invention provides a pharmaceuticalcomposition which contains a compound of Formula I or a N-oxidederivative, individual isomers and mixture of isomers thereof, or apharmaceutically acceptable salt thereof, in admixture with one or moresuitable excipients.

In a third aspect, the present invention provides a method of treating adisease in an animal in which inhibition of kinase activity,particularly Abl, BCR-Abl, PDGF-R, trkB, c-SRC, BMX, FGFR3, B-RAF, SGK,Tie2, Lck, JNK2α2, MKK4, c-RAF, MKK6, SAPK2α and/or SAPK2β activity, canprevent, inhibit or ameliorate the pathology and/or symptomology of thediseases, which method comprises administering to the animal atherapeutically effective amount of a compound of Formula I or a N-oxidederivative, individual isomers and mixture of isomers thereof, or apharmaceutically acceptable salt thereof.

In a fourth aspect, the present invention provides the use of a compoundof Formula I in the manufacture of a medicament for treating a diseasein an animal in which kinase activity, particularly Abl, BCR-Abl,PDGF-R, trkB, c-SRC, BMX, FGFR3, B-RAF, SGK, Tie2, Lck, JNK2α2, MKK4,c-RAF, MKK6, SAPK2α and/or SAPK2β activity, contributes to the pathologyand/or symptomology of the disease.

In a fifth aspect, the present invention provides a process forpreparing compounds of Formula I and the N-oxide derivatives, prodrugderivatives, protected derivatives, individual isomers and mixture ofisomers thereof, and the pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION Definitions

“Alkyl” as a group and as a structural element of other groups, forexample halo-substituted-alkyl and alkoxy, can be eitherstraight-chained or branched. C₁₋₄-alkoxy includes, methoxy, ethoxy, andthe like. Halo-substituted alkyl includes trifluoromethyl,pentafluoroethyl, and the like.

“Aryl” means a monocyclic or fused bicyclic aromatic ring assemblycontaining six to ten ring carbon atoms. For example, aryl may be phenylor naphthyl, preferably phenyl. “Arylene” means a divalent radicalderived from an aryl group.

“Heteroaryl” is as defined for aryl above where one or more of the ringmembers is a heteroatom. For example heteroaryl includes pyridyl,indolyl, indazolyl, quinoxalinyl, quinolinyl, benzofuranyl,benzopyranyl, benzothiopyranyl, benzo[1,3]dioxole, imidazolyl,benzo-imidazolyl, pyrimidinyl, furanyl, oxazolyl, isoxazolyl, triazolyl,tetrazolyl, pyrazolyl, thienyl, etc.

“Cycloalkyl” means a saturated or partially unsaturated, monocyclic,fused bicyclic or bridged polycyclic ring assembly containing the numberof ring atoms indicated. For example, C₃₋₁₀cycloalkyl includescyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

“Heterocycloalkyl” means cycloalkyl, as defined in this application,provided that one or more of the ring carbons indicated, are replaced bya moiety selected from —O—, —N═, —NR—, —C(O)—, —S—, —S(O)— or —S(O)₂—,wherein R is hydrogen, C₁₋₄ alkyl or a nitrogen protecting group. Forexample, C₃₋₈heterocycloalkyl as used in this application to describecompounds of the invention includes morpholino, pyrrolidinyl,pyrrolidinyl-2-one, piperazinyl, piperidinyl, piperidinylone,1,4-dioxa-8-aza-spiro[4.5]dec-8-yl, etc.

“Halogen” (or halo) preferably represents chloro or fluoro, but may alsobe bromo or iodo.

“Mutant forms of BCR-Abl” means single or multiple amino acid changesfrom the wild-type sequence. Over 22 mutations have been reported todate with the most common being G250E, E255V, T315I, F317L and M351T.

“Treat”, “treating” and “treatment” refer to a method of alleviating orabating a disease and/or its attendant symptoms.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The fusion protein BCR-Abl is a result of a reciprocal translocationthat fuses the Abl proto-oncogene with the Bcr gene. BCR-Abl is thencapable of transforming B-cells through the increase of mitogenicactivity. This increase results in a reduction of sensitivity toapoptosis, as well as altering the adhesion and homing of CML progenitorcells. The present invention provides compounds, compositions andmethods for the treatment of kinase related disease, particularly Abl,BCR-Abl, PDGF-R, trkB, c-SRC, BMX, FGFR3, B-RAF, b-RAF, SGK, Tie2, Lck,JNK2α2, MKK4, c-RAF, MKK6, SAPK2α and SAPK2β kinase related diseases.For example, leukemia and other proliferation disorders related toBCR-Abl can be treated through the inhibition of wild type and mutantforms of Bcr-Abl.

In one embodiment, with reference to compounds of Formula I, arecompounds of Formula Ia:

in which:

p is selected from 0 and 1;

n is selected from 0, 1, 2 and 3;

q is selected from 0 and 1;

R₅ is selected from hydrogen, C₁₋₆alkyl, C₆₋₁₀aryl-C₀₋₄alkyl,C₅₋₁₀heteroaryl-C₀₋₄alkyl, C₃₋₁₀cycloalkyl-C₀₋₄alkyl andC₃₋₁₀heterocycloalkyl-C₀₋₄alkyl; and R₆ is selected hydrogen andC₁₋₆alkyl; or R₅ and R₆ together with the nitrogen to which R₅ and R₆are both attached form heteroaryl or heterocycloalkyl;

wherein any aryl, heteroaryl, cycloalkyl and heterocycloalkyl of R₅ orthe combination of R₅ and R₆ can be optionally substituted with 1 to 3radicals independently selected from halo, nitro, cyano, hydroxy,C₁₋₆alkyl, C₁₋₆alkoxy, halo-substituted-alkyl, halo-substituted-alkoxy,—XNR₇R₈, —XOR₇, —XNR₇S(O)₂R₈, —XNR₇S(O)R₈, —XNR₇SR₈, —XC(O)NR₇R₈,—XC(O)NR₇XNR₇R₈, —XNR₇C(O)NR₇R₈, —XNR₇XNR₇R₈, —XNR₇XOR₇,—XNR₇C(═NR₇)NR₇R₈, —XS(O)₂R₉, —XNR₇C(O)R₈, —XNR₇C(O)R₉, —XR₉, —XC(O)OR₈,—XS(O)₂NR₇R₈, —XS(O)NR₇R₈ and —XSNR₇R₈; wherein X is a bond orC₁₋₄alkylene; R₇ and R₈ are independently selected from the groupconsisting of hydrogen and C₁₋₄alkyl; and R₉ is selected fromC₃₋₁₀heterocycloalkyl and C₅₋₁₀heteroaryl; wherein said heterocycloalkylor heteroaryl of R₉ is optionally substituted with a radical selectedfrom the group consisting of C₁₋₄alkyl, —XNR₇XNR₇R₇, XNR₇XOR₇ and —XOR₇;wherein X and R₇ are as described above;

R₁₀ is selected from hydrogen and C₁₋₆alkyl;

R₁₅ is selected from halo, nitro, cyano, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-alkyl and halo-substituted-alkoxy; and

R₁₆ is selected from —NR₁₂C(O)R₁₃, —NR₁₂C(O)NR₁₂R₁₃, —C(O)NR₁₂R₁₃,—NR₁₂S(O)₀₋₂R₁₃ and —S(O)₀₋₂NR₁₂R₁₃; wherein R₁₂ is selected fromhydrogen and C₁₋₆ alkyl; R₁₃ is selected from C₆₋₁₀aryl,C₅₋₁₀heteroaryl, C₃₋₁₀cycloalkyl and C₃₋₁₀heterocycloalkyl; wherein anyaryl, heteroaryl, cycloalkyl or heterocycloalkyl of R₁₃ is optionallysubstituted with 1 to 3 radicals independently selected from halo,C₁₋₆alkyl, halo-substituted-C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-C₁₋₆alkoxy, —XNR₇R₈, C₆₋₁₀aryl-C₀₋₄alkyl, C₅₋₁₀heteroaryl-C₀₋₄alkyl, C₃₋₁₀cycloalkyl-C₀₋₄alkyl,C₃₋₁₀heterocycloalkyl-C₀₋₄alkoxy and C₃₋₁₀heterocycloalkyl-C₀₋₄alkyl;wherein X, R₇ and R₈ are as described above and wherein any aryl,heteroaryl, cycloalkyl or heterocycloalkyl substituent of R₁₃ is furtheroptionally substituted by 1 to 3 radicals independently selected fromhalo, C₁₋₆alkyl, halo-substituted-C₁₋₆alkyl,hydroxy-substituted-C₁₋₆alkyl, C₁₋₆alkoxy, C₃₋₁₀heterocycloalkyl andhalo-substituted-C₁₋₆alkoxy.

In another embodiment, R₅ is selected from hydrogen, morpholino-ethyl,cyclopropyl, methyl, 3-(2-oxo-pyrrolidin-1-yl)-propyl,benzo[1,3]dioxol-5-yl, 3-(4-methyl-piperazin-1-yl)-propyl,hydroxymethyl-phenyl, (1-hydroxyethyl)-phenyl, morpholino, pyridinyl,methyl-carbonyl, methyl-sulfonyl, methyl-pyridinyl, amino-cyclohexyl,piperidinyl, methyl-piperazinyl-ethyl, dimethyl-pyrazolyl,methyl-pyrazolyl, dimethyl-pyridinyl, methyl-pyridinyl,ethyl-piperazinyl-pyridinyl, amino-carbonyl-pyridinyl, cyano-pyridinyl,dimethyl-amino-ethyl, methoxy-ethyl, methyl-pyrrolidinyl-ethyl,ethyl-pyrazolyl, dimethyl-amino-propyl, isopropyl, furanyl-methyl,methyl-piperazinyl-propyl, benzo[1,3]dioxol-5-ylmethyl,2-methyl-6-morpholin-4-yl-pyridin-3-yl, methyl-pyrimidinyl,methoxy-pyridinyl, fluoro-phenyl, dimethyl-amino-ethyl-aminocarbonyl,pyridinyl-methyl, thiazolyl-methyl, methyl-pyrazinyl-methyl,imidazolyl-propyl, amino-carbonyl-phenyl, or R₅ and R₆ together with thenitrogen atom to which they are both attached form a group selected frommorpholino, piperidinyl and piperazinyl optionally substituted with agroup selected from ethyl, pyridinyl and morpholino.

In a further embodiment, R₁₆ is selected from —NHC(O)R₁₃, —NHC(O)NHR₁₃,—C(O)NHR₁₃, —NHS(O)₂R₁₃ and —S(O)₂NHR₁₃; wherein R₁₃ is selected fromphenyl, pyridazinyl, pyridinyl, furanyl, pyrrolyl, imidazolyl,pyrazolyl, quinoxalinyl, thienyl and thiazolyl; wherein R₁₃ isoptionally substituted with 1 to 3 radicals independently selected frommethyl, t-butyl, halo, trifluoromethyl, diethyl-amino, dimethyl-amino,benzyl, piperidinyl-amino, pyrrolidinyl-methoxy,ethyl-piperazinyl-methyl, morpholino, methyl-piperazinyl,methyl-piperazinyl-methyl, ethyl-piperazinyl, methyl-imidazolyl,morpholino-methyl, pyrrolidinyl-piperidinyl, piperazinyl-methyl,hydroxy-piperidinyl, 1-methyl-piperidin-4-yloxy, piperidinyl-oxy,methyl-pyrazinyl, pyrazinyl and hydroxyethyl-piperazinyl.

Preferred compounds of the invention are selected fromN-[4-methyl-3-(1-{6-[4-(2-morpholin-4-yl-ethyl)-phenylamino]-pyrimidin-4-yl}-1H-imidazol-2-ylamino)-phenyl]-3-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-(4-ethyl-piperazin-1-yl)-5-trifluoromethyl-benzamide,N-(4-methyl-3-{1-[6-(2-morpholin-4-yl-ethylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-3-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-trifluoromethyl-benzamide,N-{4-methyl-3-[1-(6-methylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-phenyl}-3-trifluoromethyl-benzamide,N-[4-methyl-3-(1-{6-[3-(2-oxo-pyrrolidin-1-yl)-propylamino]-pyrimidin-4-yl}-1H-imidazol-2-ylamino)-phenyl]-3-trifluoromethyl-benzamide,N-(3-{1-[6-(benzo[1,3]dioxol-5-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-4-methyl-phenyl)-3-trifluoromethyl-benzamide,N-[4-methyl-3-(1-{6-[3-(4-methyl-piperazin-1-yl)-propylamino]-pyrimidin-4-yl}-1H-imidazol-2-ylamino)-phenyl]-3-trifluoromethyl-benzamide,{6-[2-(2-chloro-phenylamino)-imidazol-1-yl]-pyrimidin-4-yl}-cyclopropyl-amine,(3-{6-[2-(2-chloro-phenylamino)-imidazol-1-yl]-pyrimidin-4-ylamino}-phenyl)-methanol,1-(3-{6-[2-(2-chloro-phenylamino)-imidazol-1-yl]-pyrimidin-4-ylamino}-phenyl)-ethanol,{6-[2-(2-chloro-phenylamino)-imidazol-1-yl]-pyrimidin-4-yl}-[4-(2-morpholin-4-yl-ethyl)-phenyl]-amine,{6-[2-(2-chloro-phenylamino)-imidazol-1-yl]-pyrimidin-4-yl}-(4-morpholin-4-yl-phenyl)-amine,N-(3-{6-[2-(2-chloro-phenylamino)-imidazol-1-yl]-pyrimidin-4-ylamino}-phenyl)-acetamide,1-(3-{6-[2-(2-chloro-phenylamino)-imidazol-1-yl]-pyrimidin-4-ylamino}-propyl)-pyrrolidin-2-one,benzo[1,3]dioxol-5-yl-{6-[2-(2-chloro-phenylamino)-imidazol-1-yl]-pyrimidin-4-yl}-amine,{6-[2-(2-chloro-phenylamino)-imidazol-1-yl]-pyrimidin-4-yl}-pyridin-3-yl-amine,N-(4-methyl-3-{1-[6-(pyridin-3-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-3-trifluoromethyl-benzamide,{6-[2-(2-chloro-phenylamino)-imidazol-1-yl]-pyrimidin-4-yl}-(6-methyl-pyridin-3-yl)-amine,N-(4-methyl-3-{1-[6-(6-methyl-pyridin-3-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-3-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-morpholin-4-yl-5-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-(4-methyl-piperazin-1-yl)-5-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-(4-ethyl-piperazin-1-yl)-5-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-4-morpholin-4-yl-3-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzamide,3-(4-methyl-imidazol-1-yl)-N-{4-methyl-3-[1-(6-methylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-phenyl}-5-trifluoromethyl-benzamide,N-{4-methyl-3-[1-(6-methylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-phenyl}-4-morpholin-4-yl-3-trifluoromethyl-benzamide,3-(4-ethyl-piperazin-1-yl)-N-{4-methyl-3-[1-(6-methylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-phenyl}-5-trifluoromethyl-benzamide,N-{4-methyl-3-[1-(6-methylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-phenyl}-3-(4-methyl-piperazin-1-yl)-5-trifluoromethyl-benzamide,N-{3-[1-(6-methylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-phenyl}-4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzamide,3-(4-ethyl-piperazin-1-ylmethyl)-N-{4-methyl-3-[1-(6-methylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-phenyl}-5-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-4-morpholin-4-ylmethyl-3-trifluoromethyl-benzamide,N-{4-methyl-3-[1-(6-methylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-phenyl}-4-morpholin-4-ylmethyl-3-trifluoromethyl-benzamide,N-{3-[1-(6-amino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzamide,N-{3-[1-(6-amino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzamide,N-{3-[1-(6-amino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-phenyl}-3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzamide,N-{3-[1-(6-amino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-4-morpholin-4-yl-3-trifluoromethyl-benzamide,N-{3-[1-(6-amino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-(4-ethyl-piperazin-1-yl)-5-trifluoromethyl-benzamide,N-{3-[1-(6-amino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-(4-methyl-piperazin-1-yl)-5-trifluoromethyl-benzamide,N-{3-[1-(6-amino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-morpholin-4-ylmethyl-5-trifluoromethyl-benzamide,3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-5-methoxy-N-[4-(2-methyl-imidazol-1-yl)-3-trifluoromethyl-phenyl]-benzamide,N-{3-[1-(6-acetylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-trifluoromethyl-benzamide,N-{3-[1-(6-methanesulfonylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-trifluoromethyl-benzamide,N-{3-[1-(2-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-trifluoromethyl-benzamide,3-[1-(2-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-N-[4-(2-methyl-imidazol-1-yl)-3-trifluoromethyl-phenyl]-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-piperazin-1-ylmethyl-5-trifluoromethyl-benzamide,N-{3-[1-(6-amino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-piperazin-1-ylmethyl-5-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-5-methoxy-phenyl}-4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-5-methoxy-phenyl}-3-(4-ethyl-piperazin-1-ylmethyl)-5-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-(piperidin-4-yloxy)-5-trifluoromethyl-benzamide,N-{3-[1-(6-amino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-(piperidin-4-yloxy)-5-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-5-methoxy-phenyl}-3-(4-pyrrolidin-1-yl-piperidin-1-yl)-5-trifluoromethyl-benzamide,1-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-[4-(2-methyl-imidazol-1-yl)-3-trifluoromethyl-phenyl]-urea,1-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-[4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-urea,pyridazine-4-carboxylic acid{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-amide,2-chloro-N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-isonicotinamide,furan-2-carboxylic acid{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-amide,1-methyl-1H-pyrrole-2-carboxylic acid{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-amide,1H-imidazole-2-carboxylic acid{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-amide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-4-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-6-methyl-nicotinamide,1-tert-butyl-5-methyl-1H-pyrazole-3-carboxylic acid{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-amide,N-[4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-4-methyl-3-{1-[6-(2-morpholin-4-yl-ethylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-benzamide,3-(4-methyl-imidazol-1-yl)-N-(4-methyl-3-{1-[6-(2-morpholin-4-yl-ethylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-5-trifluoromethyl-benzamide,4-methyl-N-[4-(2-methyl-imidazol-1-yl)-3-trifluoromethyl-phenyl]-3-{1-[6-(2-morpholin-4-yl-ethylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-benzamide,N-(4-methyl-3-{1-[6-(2-morpholin-4-yl-ethylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-3-(1-methyl-piperidin-4-yloxy)-5-trifluoromethyl-benzamide,pyrazine-2-carboxylic acid{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-amide,5-methyl-pyrazine-2-carboxylic acid{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-amide,quinoxaline-6-carboxylic acid{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-amide,5-tert-butyl-2-methyl-4-morpholin-4-ylmethyl-furan-3-carboxylic acid{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-amide,5-tert-butyl-2-methyl-2H-pyrazole-3-carboxylic acid{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-amide,2-benzyl-5-tert-butyl-2H-pyrazole-3-carboxylic acid{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-amide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-(piperidin-4-ylamino)-5-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-(pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-benzamide,5-tert-butyl-2-methyl-furan-3-carboxylic acid{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-amide,5-tert-butyl-3-methyl-furan-2-carboxylic acid{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-amide,5-tert-butyl-2-diethylamino-furan-3-carboxylic acid{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-amide,5-tert-butyl-4-diethylamino-2-methyl-furan-3-carboxylic acid{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-amide,5-tert-butyl-thiophene-2-carboxylic acid{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-amide,5-tert-butyl-3-methyl-furan-2-carboxylic acid(4-methyl-3-{1-[6-(2-morpholin-4-yl-ethylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-amide,5-tert-butyl-thiophene-2-carboxylic acid(4-methyl-3-{1-[6-(2-morpholin-4-yl-ethylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-amide,5-tert-butyl-2-methyl-furan-3-carboxylic acid(4-methyl-3-{1-[6-(2-morpholin-4-yl-ethylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-amide,N-(3-{1-[6-(4-amino-cyclohexylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-4-methyl-phenyl)-3-trifluoromethyl-benzamide,N-(4-methyl-3-{1-[6-(piperidin-4-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-3-trifluoromethyl-benzamide,N-[4-methyl-3-(1-{6-[2-(4-methyl-piperazin-1-yl)-ethylamino]-pyrimidin-4-yl}-1H-imidazol-2-ylamino)-phenyl]-3-trifluoromethyl-benzamide,N-(3-{1-[6-(2,5-dimethyl-2H-pyrazol-3-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-4-methyl-phenyl)-3-trifluoromethyl-benzamide,N-(4-methyl-3-{1-[6-(4-methyl-piperazin-1-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-3-trifluoromethyl-benzamide,N-(4-methyl-3-{1-[6-(2-methyl-2H-pyrazol-3-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-3-trifluoromethyl-benzamide,N-(3-{1-[6-(2,6-dimethyl-pyridin-3-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-4-methyl-phenyl)-3-trifluoromethyl-benzamide,N-(4-methyl-3-{1-[6-(2-methyl-pyridin-3-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-3-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-(4-methyl-piperazin-1-yl)-5-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-5-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-piperazin-1-yl-5-trifluoromethyl-benzamide,N-{4-chloro-3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-phenyl}-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-fluoro-phenyl}-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-2-methyl-phenyl}-benzamide,N-{5-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-2-fluoro-phenyl}-benzamide,N-{5-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-2-methyl-phenyl}-benzamide,N-{4-chloro-3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-phenyl}-4-morpholin-4-ylmethyl-3-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-fluoro-phenyl}-4-morpholin-4-ylmethyl-3-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-2-methyl-phenyl}-4-morpholin-4-ylmethyl-3-trifluoromethyl-benzamide,N-{4-chloro-3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-phenyl}-3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-fluoro-phenyl}-3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-2-methyl-phenyl}-3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzamide,N-{5-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-2-fluoro-phenyl}-3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzamide,N-{5-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-2-methyl-phenyl}-3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]4-methoxy-phenyl}-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-trifluoromethyl-benzenesulfonamide,3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-N-(3-trifluoromethyl-phenyl)-benzenesulfonamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-fluoro-phenyl}-3-dimethylamino-5-trifluoromethyl-benzamide,N-{5-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-2-methyl-phenyl}-3-dimethylamino-5-trifluoromethyl-benzamide,N-{4-chloro-3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-phenyl}-3-dimethylamino-5-trifluoromethyl-benzamide,3-(4-methyl-imidazol-1-yl)-N-(4-methyl-3-{1-[6-(pyridin-2-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-5-trifluoromethyl-benzamide,4-(4-ethyl-piperazin-1-ylmethyl)-N-(4-methyl-3-{1-[6-(pyridin-2-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-3-trifluoromethyl-benzamide,3-(4-ethyl-piperazin-1-yl)-N-(4-methyl-3-{1-[6-(pyridin-2-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-5-trifluoromethyl-benzamide,4-chloro-N-(4-methyl-3-{1-[6-(pyridin-2-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-3-trifluoromethyl-benzamide,N-[3-(1-{6-[5-(4-ethyl-piperazin-1-yl)-pyridin-2-ylamino]-pyrimidin-4-yl}-1H-imidazol-2-ylamino)-4-methyl-phenyl]-3-trifluoromethyl-benzamide,N-(4-methyl-3-{1-[6-(4-methyl-pyridin-2-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-3-trifluoromethyl-benzamide,N-(3-{1-[6-(4,6-dimethyl-pyridin-2-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-4-methyl-phenyl)-3-trifluoromethyl-benzamide,6-(6-{2-[2-methyl-5-(3-trifluoromethyl-benzoylamino)-phenylamino]-imidazol-1-yl}-pyrimidin-4-ylamino)-nicotinamide,N-(4-methyl-3-{1-[6-(5-methyl-pyridin-2-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-3-trifluoromethyl-benzamide,N-(3-{1-[6-(5-cyano-pyridin-2-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-4-methyl-phenyl)-3-trifluoromethyl-benzamide,4-chloro-N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-trifluoromethyl-benzamide,4-chloro-N-(4-methyl-3-{1-[6-(2-morpholin-4-yl-ethylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-3-trifluoromethyl-benzamide,5-tert-butyl-2-methyl-2H-pyrazole-3-carboxylic acid(4-methyl-3-{1-[6-(2-morpholin-4-yl-ethylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-amide,N-(3-{1-[6-(2-dimethylamino-ethylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-4-methyl-phenyl)-3-trifluoromethyl-benzamide,N-(4-methyl-3-{1-[6-(3-morpholin-4-yl-propylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-3-trifluoromethyl-benzamide,N-(3-{1-[6-(2-methoxy-ethylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-4-methyl-phenyl)-3-trifluoromethyl-benzamide,N-[4-methyl-3-(1-{6-[2-(1-methyl-pyrrolidin-2-yl)-ethylamino]-pyrimidin-4-yl}-1H-imidazol-2-ylamino)-phenyl]-3-trifluoromethyl-benzamide,N-(4-methyl-3-{1-[6-(pyridin-2-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-3-trifluoromethyl-benzamide,N-[4-methyl-3-(1-pyrimidin-4-yl-1H-imidazol-2-ylamino)-phenyl]-3-trifluoromethyl-benzamide,N-[4-methyl-3-(1-pyrimidin-2-yl-1H-imidazol-2-ylamino)-phenyl]-3-trifluoromethyl-benzamide,N-{4-methyl-3-[1-(4-methylamino-pyrimidin-2-yl)-1H-imidazol-2-ylamino]-phenyl}-3-trifluoromethyl-benzamide,N-{4-methyl-3-[1-(2-methylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-phenyl}-3-trifluoromethyl-benzamide,N-(4-methyl-3-{1-[4-(2-morpholin-4-yl-ethylamino)-pyrimidin-2-yl]-1H-imidazol-2-ylamino}-phenyl)-3-trifluoromethyl-benzamide,N-(4-methyl-3-{1-[2-(2-morpholin-4-yl-ethylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-3-trifluoromethyl-benzamide,N-(3-{1-[6-(2-ethyl-2H-pyrazol-3-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-4-methyl-phenyl)-3-trifluoromethyl-benzamide,N-(3-{1-[6-(3-dimethylamino-propylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-4-methyl-phenyl)-3-trifluoromethyl-benzamide,N-{3-[1-(6-isopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-trifluoromethyl-benzamide,N-[3-(1-{6-[(furan-3-ylmethyl)-amino]-pyrimidin-4-yl}-1H-imidazol-2-ylamino)-4-methyl-phenyl]-3-trifluoromethyl-benzamide,N-[4-methyl-3-(1-{6-[3-(4-methyl-piperazin-1-yl)-propylamino]-pyrimidin-4-yl}-1H-imidazol-2-ylamino)-phenyl]-3-trifluoromethyl-benzamide,N-[3-(1-{6-[(benzo[1,3]dioxol-5-ylmethyl)-amino]-pyrimidin-4-yl}1H-imidazol-2-ylamino)-4-methyl-phenyl]-3-trifluoromethyl-benzamide,N-(4-methyl-3-{1-[6-(2-methyl-6-morpholin-4-yl-pyridin-3-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-3-trifluoromethyl-benzamide,N-(4-methyl-3-{1-[6-(4-methyl-pyrimidin-2-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-3-trifluoromethyl-benzamide,N-(3-{1-[6-(6-methoxy-pyridin-3-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-4-methyl-phenyl)-3-trifluoromethyl-benzamide,N-{4-methyl-3-[1-(6-morpholin-4-yl-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-phenyl}-3-trifluoromethyl-benzamide,N-(3-{1-[6-(4-ethyl-piperazin-1-yl)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-4-methyl-phenyl)-3-trifluoromethyl-benzamide,N-(3-{1-[6-(3-fluoro-phenylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-4-methyl-phenyl)-3-trifluoromethyl-benzamide,N-(3-{1-[6-(3-dimethylamino-ethyl-formamide-phenylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-4-methyl-phenyl)-3-trifluoromethyl-benzamide,N-[4-methyl-3-(1-{6-[(pyridin-3-ylmethyl)-amino]-pyrimidin-4-yl}-1H-imidazol-2-ylamino)-phenyl]-3-trifluoromethyl-benzamide,N-[4-methyl-3-(1-{6-[(pyridin-4-ylmethyl)-amino]-pyrimidin-4-yl}-1H-imidazol-2-ylamino)-phenyl]-3-trifluoromethyl-benzamide,N-(4-methyl-3-{1-[6-(4-morpholin-4-yl-piperidin-1-yl)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-3-trifluoromethyl-benzamide,N-[4-methyl-3-(1-{6-[(thiazol-2-ylmethyl)-amino]-pyrimidin-4-yl}-1H-imidazol-2-ylamino)-phenyl]-3-trifluoromethyl-benzamide,N-[4-methyl-3-(1-{6-[(pyridin-2-ylmethyl)-amino]-pyrimidin-4-yl}-1H-imidazol-2-ylamino)-phenyl]-3-trifluoromethyl-benzamide,N-[4-methyl-3-(1-{6-[(6-methyl-pyrazin-2-ylmethyl)-amino]-pyrimidin-4-yl}-1H-imidazol-2-ylamino)-phenyl]-3-trifluoromethyl-benzamide,N-(4-methyl-3-{1-[6-(4-pyridin-2-yl-piperazin-1-yl)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-3-trifluoromethyl-benzamide,N-(3-{1-[6-(3-imidazol-1-yl-propylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-4-methyl-phenyl)-3-trifluoromethyl-benzamide,N-(4-methyl-3-{1-[6-(pyrazin-2-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-3-trifluoromethyl-benzamide,N-(3-{1-[6-(3-formamide-phenylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-4-methyl-phenyl)-3-trifluoromethyl-benzamide,4-methyl-3-{1-[6-(2-morpholin-4-yl-ethylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-N-(3-trifluoromethyl-phenyl)-benzamide,4-methyl-3-{1-[6-(4-methyl-piperazin-1-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-N-(3-trifluoromethyl-phenyl)-benzamide,N-(4-chloro-3-trifluoroethyl-phenyl)-4-methyl-3-{1-[6-(2-morpholin-4-yl-ethylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-benzamide,N-(4-chloro-3-trifluoromethyl-phenyl)-4-methyl-3-{1-[6-(4-methyl-piperazin-1-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-benzamide,1-tert-butyl-5-(4-methyl-piperazin-1-ylmethyl)-1H-pyrazole-3-carboxylicacid{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-amide,1-tert-butyl-5-morpholin-4-ylmethyl-1H-pyrazole-3-carboxylic acid{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-amide,N-(4-tert-butyl-thiazol-2-yl)-4-methyl-3-{1-[6-(2-morpholin-4-yl-ethylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-benzamide,N-(4-tert-butyl-thiazol-2-yl)-4-methyl-3-{1-[6-(4-methyl-piperazin-1-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-benzamide,N-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-4-methyl-3-{1-[6-(4-methyl-piperazin-1-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-benzamide,N-(4-methyl-3-{1-[6-(4-methyl-piperazin-1-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-benzamide,N-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-4-methyl-3-{1-[6-(2-morpholin-4-yl-ethylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-benzamide,N-(4-methyl-3-{1-[2-(2-morpholin-4-yl-ethylamino)-pyridin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-3-trifluoromethyl-benzamide,N-{3-[1-(4-acetylamino-pyridin-2-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-trifluoromethyl-benzamideand2-{2-[2-Methyl-5-(3-trifluoromethyl-benzoylamino)-phenylamino]-imidazol-1-yl}-isonicotinamide.

Further preferred compounds of the invention are detailed in theExamples and Table I, infra.

Pharmacology and Utility

Compounds of the invention modulate the activity of kinases and, assuch, are useful for treating diseases or disorders in which kinases,contribute to the pathology and/or symptomology of the disease. Examplesof kinases that are inhibited by the compounds and compositionsdescribed herein and against which the methods described herein areuseful include, but are not limited to, Abl, BCR-Abl (wild-type andmutant forms), PDGF-R, trkB, c-SRC, BMX, FGFR3, b-RAF, SGK, Tie2, Lck,JNK2α2, MKK4, c-RAF, MKK6, SAPK2α and SAPK2β.

Abelson tyrosine kinase (i.e. Abl, c-Abl) is involved in the regulationof the cell cycle, in the cellular response to genotoxic stress, and inthe transmission of information about the cellular environment throughintegrin signaling. Overall, it appears that the Abl protein serves acomplex role as a cellular module that integrates signals from variousextracellular and intracellular sources and that influences decisions inregard to cell cycle and apoptosis. Abelson tyrosine kinase includessub-types derivatives such as the chimeric fusion (oncoprotein) BCR-Ablwith deregulated tyrosine kinase activity or the v-Abl. BCR-Abl iscritical in the pathogenesis of 95% of chronic myelogenous leukemia(CML) and 10% of acute lymphocytic leukemia. STI-571 (Gleevec) is aninhibitor of the oncogenic BCR-Abl tyrosine kinase and is used for thetreatment of chronic myeloid leukemia (CML). However, some patients inthe blast crisis stage of CML are resistant to STI-571 due to mutationsin the BCR-Abl kinase. Over 22 mutations have been reported to date withthe most common being G250E, E255V, T315I, F317L and M351T.

Compounds of the present invention inhibit abl kinase, especially v-ablkinase. The compounds of the present invention also inhibit wild-typeBCR-Abl kinase and mutations of BCR-Abl kinase and are thus suitable forthe treatment of Bcr-abl-positive cancer and tumor diseases, such asleukemias (especially chronic myeloid leukemia and acute lymphoblasticleukemia, where especially apoptotic mechanisms of action are found),and also shows effects on the subgroup of leukemic stem cells as well aspotential for the purification of these cells in vitro after removal ofsaid cells (for example, bone marrow removal) and reimplantation of thecells once they have been cleared of cancer cells (for example,reimplantation of purified bone marrow cells).

The Ras-Raf-MEK-ERK signaling pathway mediates cellular response togrowth signals. Ras is mutated to an oncogenic form in ˜15% of humancancer. The Raf family belongs to the serine/threonine protein kinaseand it includes three members, A-Raf, B-Raf and c-Raf (or Raf-1). Thefocus on Raf being a drug target has centered on the relationship of Rafas a downstream effector of Ras. However, recent data suggests thatB-Raf may have a prominent role in the formation of certain tumors withno requirement for an activated Ras allele (Nature 417, 949-954 (1 Jul.2002). In particular, B-Raf mutations have been detected in a largepercentage of malignant melanomas.

Existing medical treatments for melanoma are limited in theireffectiveness, especially for late stage melanomas. The compounds of thepresent invention also inhibit cellular processes involving b-Rafkinase, providing a new therapeutic opportunity for treatment of humancancers, especially for melanoma.

The compounds of the present invention also inhibit cellular processesinvolving c-Raf kinase. c-Raf is activated by the ras oncogene, which ismutated in a wide number of human cancers. Therefore inhibition of thekinase activity of c-Raf may provide a way to prevent ras mediated tumorgrowth [Campbell, S. L., Oncogene, 17, 1395 (1998)].

PDGF (Platelet-derived Growth Factor) is a very commonly occurringgrowth factor, which plays an important role both in normal growth andalso in pathological cell proliferation, such as is seen incarcinogenesis and in diseases of the smooth-muscle cells of bloodvessels, for example in atherosclerosis and thrombosis. Compounds of theinvention can inhibit PDGF receptor (PDGFR) activity and are, therefore,suitable for the treatment of tumor diseases, such as gliomas, sarcomas,prostate tumors, and tumors of the colon, breast, and ovary.

Compounds of the present invention, can be used not only as atumor-inhibiting substance, for example in small cell lung cancer, butalso as an agent to treat non-malignant proliferative disorders, such asatherosclerosis, thrombosis, psoriasis, scleroderma and fibrosis, aswell as for the protection of stem cells, for example to combat thehemotoxic effect of chemotherapeutic agents, such as 5-fluoruracil, andin asthma. Compounds of the invention can especially be used for thetreatment of diseases, which respond to an inhibition of the PDGFreceptor kinase.

Compounds of the present invention show useful effects in the treatmentof disorders arising as a result of transplantation, for example,allogenic transplantation, especially tissue rejection, such asespecially obliterative bronchiolitis (OB), i.e. a chronic rejection ofallogenic lung transplants. In contrast to patients without OB, thosewith OB often show an elevated PDGF concentration in bronchoalveolarlavage fluids.

Compounds of the present invention are also effective in diseasesassociated with vascular smooth-muscle cell migration and proliferation(where PDGF and PDGF-R often also play a role), such as restenosis andatherosclerosis. These effects and the consequences thereof for theproliferation or migration of vascular smooth-muscle cells in vitro andin vivo can be demonstrated by administration of the compounds of thepresent invention, and also by investigating its effect on thethickening of the vascular intima following mechanical injury in vivo.

The trk family of neurotrophin receptors (trkA, trkB, trkC) promotes thesurvival, growth and differentiation of the neuronal and non-neuronaltissues. The trkB protein is expressed in neuroendocrine-type cells inthe small intestine and colon, in the alpha cells of the pancreas, inthe monocytes and macrophages of the lymph nodes and of the spleen, andin the granular layers of the epidermis (Shibayama and Koizumi, 1996).Expression of the TrkB protein has been associated with an unfavorableprogression of Wilms tumors and of neuroblastomas. TkrB is, moreover,expressed in cancerous prostate cells but not in normal cells. Thesignaling pathway downstream of the trk receptors involves the cascadeof MAPK activation through the Shc, activated Ras, ERK-1 and ERK-2genes, and the PLC-gammal transduction pathway (Sugimoto et al., 2001).

The kinase, c-Src transmits oncogenic signals of many receptors. Forexample, over-expression of EGFR or HER2/neu in tumors leads to theconstitutive activation of c-src, which is characteristic for themalignant cell but absent from the normal cell. On the other hand, micedeficient in the expression of c-src exhibit an osteopetrotic phenotype,indicating a key participation of c-src in osteoclast function and apossible involvement in related disorders.

The Tec family kinase, Bmx, a non-receptor protein-tyrosine kinase,controls the proliferation of mammary epithelial cancer cells.

Fibroblast growth factor receptor 3 was shown to exert a negativeregulatory effect on bone growth and an inhibition of chondrocyteproliferation. Thanatophoric dysplasia is caused by different mutationsin fibroblast growth factor receptor 3, and one mutation, TDII FGFR3,has a constitutive tyrosine kinase activity which activates thetranscription factor Stat1, leading to expression of a cell-cycleinhibitor, growth arrest and abnormal bone development (Su et al.,Nature, 1997, 386, 288-292). FGFR3 is also often expressed in multiplemyeloma-type cancers. Inhibitors of FGFR3 activity are useful in thetreatment of T-cell mediated inflammatory or autoimmune diseasesincluding but not limited to rheumatoid arthritis (RA), collagen IIarthritis, multiple sclerosis (MS), systemic lupus erythematosus (SLE),psoriasis, juvenile onset diabetes, Sjogren's disease, thyroid disease,sarcoidosis, autoimmune uveitis, inflammatory bowel disease (Crohn's andulcerative colitis), celiac disease and myasthenia gravis.

The activity of serum and glucocorticoid-regulated kinase (SGK), iscorrelated to perturbed ion-channel activities, in particular, those ofsodium and/or potassium channels and compounds of the invention can beuseful for treating hypertension.

Lin et al (1997) J. Clin. Invest. 100, 8: 2072-2078 and P. Lin (1998)PNAS 95, 8829-8834, have shown an inhibition of tumor growth andvascularization and also a decrease in lung metastases during adenoviralinfections or during injections of the extracellular domain of Tie-2(Tek) in breast tumor and melanoma xenograft models. Tie2 inhibitors canbe used in situations where neovascularization takes placeinappropriately (i.e. in diabetic retinopathy, chronic inflammation,psoriasis, Kaposi's sarcoma, chronic neovascularization due to maculardegeneration, rheumatoid arthritis, infantile haemangioma and cancers).

Lck plays a role in T-cell signaling. Mice that lack the Lck gene have apoor ability to develop thymocytes. The function of Lck as a positiveactivator of T-cell signaling suggests that Lck inhibitors may be usefulfor treating autoimmune disease such as rheumatoid arthritis.

JNKs, along with other MAPKs, have been implicated in having a role inmediating cellular response to lancer, thrombin-induced plateletaggregation, immunodeficiency disorders, autoimmune diseases, celldeath, allergies, osteoporosis and heart disease. The therapeutictargets related to activation of the JNK pathway include chronicmyelogenous leukemia (CML), rheumatoid arthritis, asthma,osteoarthritis, ischemia, cancer and neurodegenerative diseases. As aresult of the importance of JNK activation associated with liver diseaseor episodes of hepatic ischemia, compounds of the invention may also beuseful to treat various hepatic disorders. A role for JNK incardiovascular disease such as myocardial infarction or congestive heartfailure has also been reported as it has been shown JNK mediateshypertrophic responses to various forms of cardiac stress. It has beendemonstrated that the JNK cascade also plays a role in T-cellactivation, including activation of the IL-2 promoter. Thus, inhibitorsof JNK may have therapeutic value in altering pathologic immuneresponses. A role for JNK activation in various cancers has also beenestablished, suggesting the potential use of JNK inhibitors in cancer.For example, constitutively activated JNK is associated with HTLV-1mediated tumorigenesis [Oncogene 13:135-42 (1996)]. JNK may play a rolein Kaposi's sarcoma (KS). Other proliferative effects of other cytokinesimplicated in KS proliferation, such as vascular endothelial growthfactor (VEGF), IL-6 and TNFα, may also be mediated by JNK. In addition,regulation of the c-jun gene in p210 BCR-ABL transformed cellscorresponds with activity of JNK, suggesting a role for JNK inhibitorsin the treatment for chronic myelogenous leukemia (CML) [Blood92:2450-60 (1998)].

Certain abnormal proliferative conditions are believed to be associatedwith raf expression and are, therefore, believed to be responsive toinhibition of raf expression. Abnormally high levels of expression ofthe raf protein are also implicated in transformation and abnormal cellproliferation. These abnormal proliferative conditions are also believedto be responsive to inhibition of raf expression. For example,expression of the c-raf protein is believed to play a role in abnormalcell proliferation since it has been reported that 60% of all lungcarcinoma cell lines express unusually high levels of c-raf mRNA andprotein. Further examples of abnormal proliferative conditions arehyper-proliferative disorders such as cancers, tumors, hyperplasia,pulmonary fibrosis, angiogenesis, psoriasis, atherosclerosis and smoothmuscle cell proliferation in the blood vessels, such as stenosis orrestenosis following angioplasty. The cellular signaling pathway ofwhich raf is a part has also been implicated in inflammatory disorderscharacterized by T-cell proliferation (T-cell activation and growth),such as tissue graft rejection, endotoxin shock, and glomerularnephritis, for example.

The stress activated protein kinases (SAPKs) are a family of proteinkinases that represent the penultimate step in signal transductionpathways that result in activation of the c-jun transcription factor andexpression of genes regulated by c-jun. In particular, c-jun is involvedin the transcription of genes that encode proteins involved in therepair of DNA that is damaged due to genotoxic insults. Therefore,agents that inhibit SAPK activity in a cell prevent DNA repair andsensitize the cell to agents that induce DNA damage or inhibit DNAsynthesis and induce apoptosis of a cell or that inhibit cellproliferation.

Mitogen-activated protein kinases (MAPKs) are members of conservedsignal transduction pathways that activate transcription factors,translation factors and other target molecules in response to a varietyof extracellular signals. MAPKs are activated by phosphorylation at adual phosphorylation motif having the sequence Thr-X-Tyr bymitogen-activated protein kinase kinases (MKKs). In higher eukaryotes,the physiological role of MAPK signaling has been correlated withcellular events such as proliferation, oncogenesis, development anddifferentiation. Accordingly, the ability to regulate signaltransduction via these pathways (particularly via MKK4 and MKK6) couldlead to the development of treatments and preventive therapies for humandiseases associated with MAPK signaling, such as inflammatory diseases,autoimmune diseases and cancer.

The family of human ribosomal S6 protein kinases consists of at least 8members (RSK1, RSK2, RSK3, RSK4, MSK1, MSK2, p70S6K and p70S6 Kb).Ribosomal protein S6 protein kinases play important pleotropicfunctions, among them is a key role in the regulation of mRNAtranslation during protein biosynthesis (Eur. J. Biochem 2000 November;267(21): 6321-30, Exp Cell Res. Nov. 25, 1999; 253 (1):100-9, Mol CellEndocrinol. May 25, 1999; 151(1-2):65-77). The phosphorylation of the S6ribosomal protein by p70S6 has also been implicated in the regulation ofcell motility (Immunol. Cell Biol. 2000 August; 78(4):447-51) and cellgrowth (Prog. Nucleic Acid Res. Mol. Biol., 2000; 65:101-27), and hence,may be important in tumor metastasis, the immune response and tissuerepair as well as other disease conditions.

The SAPK's (also called “jun N-terminal kinases” or “JNK's”) are afamily of protein kinases that represent the penultimate step in signaltransduction pathways that result in activation of the c-juntranscription factor and expression of genes regulated by c-jun. Inparticular, c-jun is involved in the transcription of genes that encodeproteins involved in the repair of DNA that is damaged due to genotoxicinsults. Agents that inhibit SAPK activity in a cell prevent DNA repairand sensitize the cell to those cancer therapeutic modalities that actby inducing DNA damage.

BTK plays a role in autoimmune and/or inflammatory disease such assystemic lupus erythematosus (SLE), rheumatoid arthritis, multiplevasculitides, idiopathic thrombocytopenic purpura (ITP), myastheniagravis, and asthma. Because of BTK's role in B-cell activation,inhibitors of BTK are useful as inhibitors of B-cell mediated pathogenicactivity, such as autoantibody production, and are useful for thetreatment of B-cell lymphoma and leukemia.

CHK2 is a member of the checkpoint kinase family of serine/threonineprotein kinases and is involved in a mechanism used for surveillance ofDNA damage, such as damage caused by environmental mutagens andendogenous reactive oxygen species. As a result, it is implicated as atumor suppressor and target for cancer therapy.

CSK influences the metastatic potential of cancer cells, particularlycolon cancer.

Fes is a non-receptor protein tyrosine kinase that has been implicatedin a variety of cytokine signal transduction pathways, as well asdifferentiation of myeloid cells. Fes is also a key component of thegranulocyte differentiation machinery.

Flt3 receptor tyrosine kinase activity is implicated in leukemias andmyelodysplastic syndrome. In approximately 25% of AML the leukemia cellsexpress a constitutively active form of auto-phosphorylated (p) FLT3tyrosine kinase on the cell surface. The activity of p-FLT3 confersgrowth and survival advantage on the leukemic cells. Patients with acuteleukemia, whose leukemia cells express p-FLT3 kinase activity, have apoor overall clinical outcome. Inhibition of p-FLT3 kinase activityinduces apoptosis (programmed cell death) of the leukemic cells.

Inhibitors of IKKα and IKKβ (1 & 2) are therapeutics for diseases whichinclude rheumatoid arthritis, transplant rejection, inflammatory boweldisease, osteoarthritis, asthma, chronic obstructive pulmonary disease,atherosclerosis, psoriasis, multiple sclerosis, stroke, systemic lupuserythematosus, Alzheimer's disease, brain ischemia, traumatic braininjury, Parkinson's disease, amyotrophic lateral sclerosis, subarachnoidhemorrhage or other diseases or disorders associated with excessiveproduction of inflammatory mediators in the brain and central nervoussystem.

Met is associated with most types of the major human cancers andexpression is often correlated with poor prognosis and metastasis.Inhibitors of Met are therapeutics for diseases which include cancerssuch as lung cancer, NSCLC (non small cell lung cancer), bone cancer,pancreatic cancer, skin cancer, cancer of the head and neck, cutaneousor intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer,cancer of the anal region, stomach cancer, colon cancer, breast cancer,gynecologic tumors (e.g., uterine sarcomas, carcinoma of the fallopiantubes, carcinoma of the endometrium, carcinoma of the cervix, carcinomaof the vagina or carcinoma of the vulva), Hodgkin's Disease, cancer ofthe esophagus, cancer of the small intestine, cancer of the endocrinesystem (e.g., cancer of the thyroid, parathyroid or adrenal glands),sarcomas of soft tissues, cancer of the urethra, cancer of the penis,prostate cancer, chronic or acute leukemia, solid tumors of childhood,lymphocytic lymphomas, cancer of the bladder, cancer of the kidney orureter (e.g., renal cell carcinoma, carcinoma of the renal pelvis),pediatric malignancy, neoplasms of the central nervous system (e.g.,primary CNS lymphoma, spinal axis tumors, brain stem glioma or pituitaryadenomas), cancers of the blood such as acute myeloid leukemia, chronicmyeloid leukemia, etc, Barrett's esophagus (pre-malignant syndrome)neoplastic cutaneous disease, psoriasis, mycoses fungoides and benignprostatic hypertrophy, diabetes related diseases such as diabeticretinopathy, retinal ischemia and retinal neovascularization, hepaticcirrhosis, cardiovascular disease such as atherosclerosis, immunologicaldisease such as autoimmune disease and renal disease. Preferably, thedisease is cancer such as acute myeloid leukemia and colorectal cancer.

The Nima-related kinase 2 (Nek2) is a cell cycle-regulated proteinkinase with maximal activity at the onset of mitosis that localizes tothe centrosome. Functional studies have implicated Nek2 in regulation ofcentrosome separation and spindle formation. Nek2 protein is elevated 2-to 5-fold in cell lines derived from a range of human tumors includingthose of cervical, ovarian, prostate, and particularly breast.

p70S6K-mediated diseases or conditions include, but are not limited to,proliferative disorders, such as cancer and tuberous sclerosis.

In accordance with the foregoing, the present invention further providesa method for preventing or treating any of the diseases or disordersdescribed above in a subject in need of such treatment, which methodcomprises administering to said subject a therapeutically effectiveamount (See, “Administration and Pharmaceutical Compositions”, infra) ofa compound of Formula I or a pharmaceutically acceptable salt thereof.For any of the above uses, the required dosage will vary depending onthe mode of administration, the particular condition to be treated andthe effect desired.

Administration and Pharmaceutical Compositions

In general, compounds of the invention will be administered intherapeutically effective amounts via any of the usual and acceptablemodes known in the art, either singly or in combination with one or moretherapeutic agents. A therapeutically effective amount may vary widelydepending on the severity of the disease, the age and relative health ofthe subject, the potency of the compound used and other factors. Ingeneral, satisfactory results are indicated to be obtained systemicallyat daily dosages of from about 0.03 to 2.5 mg/kg per body weight. Anindicated daily dosage in the larger mammal, e.g. humans, is in therange from about 0.5 mg to about 100 mg, conveniently administered, e.g.in divided doses up to four times a day or in retard form. Suitable unitdosage forms for oral administration comprise from ca. 1 to 50 mg activeingredient.

Compounds of the invention can be administered as pharmaceuticalcompositions by any conventional route, in particular enterally, e.g.,orally, e.g., in the form of tablets or capsules, or parenterally, e.g.,in the form of injectable solutions or suspensions, topically, e.g., inthe form of lotions, gels, ointments or creams, or in a nasal orsuppository form. Pharmaceutical compositions comprising a compound ofthe present invention in free form or in a pharmaceutically acceptablesalt form in association with at least one pharmaceutically acceptablecarrier or diluent can be manufactured in a conventional manner bymixing, granulating or coating methods. For example, oral compositionscan be tablets or gelatin capsules comprising the active ingredienttogether with a) diluents, e.g., lactose, dextrose, sucrose, mannitol,sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum,stearic acid, its magnesium or calcium salt and/or polyethyleneglycol;for tablets also c) binders, e.g., magnesium aluminum silicate, starchpaste, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose and or polyvinylpyrrolidone; if desired d)disintegrants, e.g., starches, agar, alginic acid or its sodium salt, oreffervescent mixtures; and/or e) absorbents, colorants, flavors andsweeteners. Injectable compositions can be aqueous isotonic solutions orsuspensions, and suppositories can be prepared from fatty emulsions orsuspensions. The compositions may be sterilized and/or containadjuvants, such as preserving, stabilizing, wetting or emulsifyingagents, solution promoters, salts for regulating the osmotic pressureand/or buffers. In addition, they may also contain other therapeuticallyvaluable substances. Suitable formulations for transdermal applicationsinclude an effective amount of a compound of the present invention witha carrier. A carrier can include absorbable pharmacologically acceptablesolvents to assist passage through the skin of the host. For example,transdermal devices are in the form of a bandage comprising a backingmember, a reservoir containing the compound optionally with carriers,optionally a rate controlling barrier to deliver the compound to theskin of the host at a controlled and predetermined rate over a prolongedperiod of time, and means to secure the device to the skin. Matrixtransdermal formulations may also be used. Suitable formulations fortopical application, e.g., to the skin and eyes, are preferably aqueoussolutions, ointments, creams or gels well-known in the art. Such maycontain solubilizers, stabilizers, tonicity enhancing agents, buffersand preservatives.

Compounds of the invention can be administered in therapeuticallyeffective amounts in combination with one or more therapeutic agents(pharmaceutical combinations). For example, synergistic effects canoccur with other immunomodulatory or anti-inflammatory substances, forexample when used in combination with cyclosporin, rapamycin, orascomycin, or immunosuppressant analogues thereof, for examplecyclosporin A (CsA), cyclosporin G, FK-506, rapamycin, or comparablecompounds, corticosteroids, cyclophosphamide, azathioprine,methotrexate, brequinar, leflunomide, mizoribine, mycophenolic acid,mycophenolate mofetil, 15-deoxyspergualin, immunosuppressant antibodies,especially monoclonal antibodies for leukocyte receptors, for exampleMHC, CD2, CD3, CD4, CD7, CD25, CD28, B7, CD45, CD58 or their ligands, orother immunomodulatory compounds, such as CTLA41g. Where the compoundsof the invention are administered in conjunction with other therapies,dosages of the co-administered compounds will of course vary dependingon the type of co-drug employed, on the specific drug employed, on thecondition being treated and so forth.

The invention also provides for a pharmaceutical combinations, e.g. akit, comprising a) a first agent which is a compound of the invention asdisclosed herein, in free form or in pharmaceutically acceptable saltform, and b) at least one co-agent. The kit can comprise instructionsfor its administration.

The terms “co-administration” or “combined administration” or the likeas utilized herein are meant to encompass administration of the selectedtherapeutic agents to a single patient, and are intended to includetreatment regimens in which the agents are not necessarily administeredby the same route of administration or at the same time.

The term “pharmaceutical combination” as used herein means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that the activeingredients, e.g. a compound of Formula I and a co-agent, are bothadministered to a patient simultaneously in the form of a single entityor dosage. The term “non-fixed combination” means that the activeingredients, e.g. a compound of Formula I and a co-agent, are bothadministered to a patient as separate entities either simultaneously,concurrently or sequentially with no specific time limits, wherein suchadministration provides therapeutically effective levels of the 2compounds in the body of the patient. The latter also applies tococktail therapy, e.g. the administration of 3 or more activeingredients.

Processes for Making Compounds of the Invention

The present invention also includes processes for the preparation ofcompounds of the invention. In the reactions described, it can benecessary to protect reactive functional groups, for example hydroxy,amino, imino, thio or carboxy groups, where these are desired in thefinal product, to avoid their unwanted participation in the reactions.Conventional protecting groups can be used in accordance with standardpractice, for example, see T. W. Greene and P. G. M. Wuts in “ProtectiveGroups in Organic Chemistry”, John Wiley and Sons, 1991.

Compounds of Formula I can be prepared by proceeding as in the followingReaction Scheme I:

in which R₁, R₂, R₃, R₄, n and m are as defined for Formula I in theSummary of the Invention. A compound of Formula I can be prepared byreacting a compound of formula 2 with a compound of formula 3 in thepresence of a suitable base (e.g., DIPEA, or the like) and a suitablesolvent (e.g., butanol, THF, DMF, or the like). The reaction proceeds ina temperature range of about 80 to about 120° C. and can take up toabout 20 hours to complete.

A detailed example of the synthesis of a compound of formula I can befound in the Examples, infra.

Additional Processes for Making Compounds of the Invention

A compound of the invention can be prepared as a pharmaceuticallyacceptable acid addition salt by reacting the free base form of thecompound with a pharmaceutically acceptable inorganic or organic acid.Alternatively, a pharmaceutically acceptable base addition salt of acompound of the invention can be prepared by reacting the free acid formof the compound with a pharmaceutically acceptable inorganic or organicbase. Alternatively, the salt forms of the compounds of the inventioncan be prepared using salts of the starting materials or intermediates.

The free acid or free base forms of the compounds of the invention canbe prepared from the corresponding base addition salt or acid additionsalt from, respectively. For example a compound of the invention in anacid addition salt form can be converted to the corresponding free baseby treating with a suitable base (e.g., ammonium hydroxide solution,sodium hydroxide, and the like). A compound of the invention in a baseaddition salt form can be converted to the corresponding free acid bytreating with a suitable acid (e.g., hydrochloric acid, etc.).

Compounds of the invention in unoxidized form can be prepared fromN-oxides of compounds of the invention by treating with a reducing agent(e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride,sodium borohydride, phosphorus trichloride, tribromide, or the like) ina suitable inert organic solvent (e.g. acetonitrile, ethanol, aqueousdioxane, or the like) at 0 to 80° C.

Prodrug derivatives of the compounds of the invention can be prepared bymethods known to those of ordinary skill in the art (e.g., for furtherdetails see Saulnier et al., (1994), Bioorganic and Medicinal ChemistryLetters, Vol. 4, p. 1985). For example, appropriate prodrugs can beprepared by reacting a non-derivatized compound of the invention with asuitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbanochloridate,para-nitrophenyl carbonate, or the like).

Protected derivatives of the compounds of the invention can be made bymeans known to those of ordinary skill in the art. A detaileddescription of techniques applicable to the creation of protectinggroups and their removal can be found in T. W. Greene, “ProtectingGroups in Organic Chemistry”, 3^(rd) edition, John Wiley and Sons, Inc.,1999.

Compounds of the present invention can be conveniently prepared, orformed during the process of the invention, as solvates (e.g.,hydrates). Hydrates of compounds of the present invention can beconveniently prepared by recrystallization from an aqueous/organicsolvent mixture, using organic solvents such as dioxin, tetrahydrofuranor methanol.

Compounds of the invention can be prepared as their individualstereoisomers by reacting a racemic mixture of the compound with anoptically active resolving agent to form a pair of diastereoisomericcompounds, separating the diastereomers and recovering the opticallypure enantiomers. While resolution of enantiomers can be carried outusing covalent diastereomeric derivatives of the compounds of theinvention, dissociable complexes are preferred (e.g., crystallinediastereomeric salts). Diastereomers have distinct physical properties(e.g., melting points, boiling points, solubilities, reactivity, etc.)and can be readily separated by taking advantage of thesedissimilarities. The diastereomers can be separated by chromatography,or preferably, by separation/resolution techniques based upondifferences in solubility. The optically pure enantiomer is thenrecovered, along with the resolving agent, by any practical means thatwould not result in racemization. A more detailed description of thetechniques applicable to the resolution of stereoisomers of compoundsfrom their racemic mixture can be found in Jean Jacques, Andre Collet,Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John WileyAnd Sons, Inc., 1981.

In summary, the compounds of Formula I can be made by a process, whichinvolves:

(a) those of reaction schemes I and II, for example coupling compoundsof formula 8 with R₆YOH according to reaction scheme I; and

(b) optionally converting a compound of the invention into apharmaceutically acceptable salt;

(c) optionally converting a salt form of a compound of the invention toa non-salt form;

(d) optionally converting an unoxidized form of a compound of theinvention into a pharmaceutically acceptable N-oxide;

(e) optionally converting an N-oxide form of a compound of the inventionto its unoxidized form;

(f) optionally resolving an individual isomer of a compound of theinvention from a mixture of isomers;

(g) optionally converting a non-derivatized compound of the inventioninto a pharmaceutically acceptable prodrug derivative; and

(h) optionally converting a prodrug derivative of a compound of theinvention to its non-derivatized form.

Insofar as the production of the starting materials is not particularlydescribed, the compounds are known or can be prepared analogously tomethods known in the art or as disclosed in the Examples hereinafter.

One of skill in the art will appreciate that the above transformationsare only representative of methods for preparation of the compounds ofthe present invention, and that other well known methods can similarlybe used.

EXAMPLES

The present invention is further exemplified, but not limited, by thefollowing examples that illustrate the preparation of compounds ofFormula I according to the invention.

Example 1N-[4-methyl-3-(1-{6-[4-(2-morpholin-4-yl-ethyl)-phenylamino]-pyrimidin-4-yl}-1H-imidazol-2-ylamino)-phenyl]-3-trifluoromethyl-benzamide

N-(2,2-Diethoxyethyl)carbodiimide

A solution of the aminoacetaldehyde diethyl acetal (13.16 g, 99 mmol) inether (35 mL) was added to a suspension of CNBr (10.47 g, 99 mmol) inhexane (35 mL) at room temperature. The reaction mixture was stirred atroom temperature overnight. The solid was removed by filtration andwashed with ether. The combined filtrate was concentrated. Purificationby column chromatography (silica gel, eluting with dichloromethane to 4%methanol in dichloromethane, gradient) afforded the title compound (7.0g, 44.7%, one half of the starting amine served as a sacrificial base inthe reaction) (R_(f): 2.70, 4% methanol in dichloromethane, stain with10% ethanolic molybdatophosphoric acid). ¹H NMR 400 MHz (CDCl₃) δ 4.58(t, J=5.2 Hz, 1H), 3.77-3.69 (m, 2H), 3.65 (br, s, 1H), 3.60-352 (m,2H), 3.16 (t, J=5.6 Hz, 1H), 1.23 (t, 6H, J=6.8 Hz).

N-[3-(1H-Imidazol-2-ylamino)-4-methyl-phenyl]-3-trifluoromethyl-benzamide

A mixture of N-(2,2-diethoxyethyl)carbodiimide (398 mg, 2.51 mmol),3-amino-4-methyl-phenyl]-3-trifluoromethyl-benzamide (649 mg, 2.20mmol), methanesulfonic acid (143 μL, 2.20 mmol) in ethanol (25 mL) isheated at reflux for 16 hours. An additional portion ofN-(2,2-diethoxyethyl)carbodiimide (525 mg, 3.32 mmol) andmethanesulfonic acid (143 μL, 2.20 mmol) are added. After an additional3 hours refluxing, the reaction mixture is concentrated. The residue isdissolved in HCl (6N, 5 mL) and ethanol (5 mL). After stirringovernight, the reaction mixture is concentrated and basified with 25%NaOH solution to a pH of 14. The mixture is stirred for 30 minutes,extracted with CH₂Cl₂, dried, concentrated and purified by columnchromatography (silica gel, eluting with 7N NH₃ inmethanol:dichloromethane from 2% to 4%) to give the title compound.

N-{3-[1-(6-chloro-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-trifluoromethyl-benzamide

A mixture ofN-[3-(1H-Imidazol-2-ylamino)-4-methyl-phenyl]-3-trifluoromethyl-benzamide(330 mg, 0.92 mmol), 4,6-dichloropyrimidine (409 mg, 2.75 mmol),N,N-diisopropylethyl amine (500 μL, 2.87 mmol) in 2-butanol (20 mL) isheated at 110° C. After 16 hours, the reaction mixture is concentrated.The solid is washed with saturated sodium carbonate, water, ethylacetate, and dried to give the title compound. ¹H NMR 600 MHz (DMSO-d₆)δ 10.71 (s, 1H), 10.50 (s, 1H), 9.09 (s, 1H), 8.80 (s, 1H), 8.33 (s,1H), 8.29 (d, J=7.8 Hz, 1H), 8.17 (s, 1H), 7.96 (d, J=8.4 Hz, 1H), 7.84(s, 1H), 7.77 (t, J=8.4 Hz, 1H), 7.42 (d, J=7.2 Hz, 1H), 7.21 (d, J=8.4Hz, 1H), 6.95 (s, 1H), 2.38 (s, 3H); MS m/z 473.3 (M+1).

N-[4-methyl-3-(1-{6-[4-(2-morpholin-4-yl-ethyl)-phenylamino]-pyrimidin-4-yl}-1H-imidazol-2-ylamino)-phenyl]-3-trifluoromethyl-benzamide

A Smith vial (2-5 mL) is charged withN-{3-[1-(6-chloro-pyrimidin-4-yl)-1Himidazol-2-ylamino]-4-methyl-phenyl}-3-trifluoromethyl-benzamide (16.8mg, 0.035 mmol), 4-(2-morpholin-4-yl-ethyl)-phenylamine (22 mg, 0.11mmol), p-toluenesulfonic acid monohydrate (4.4 mg, 0.023 mmol) and DMSO(0.5 mL). After purging with Argon, the vial is sealed and irradiated at100° C. for 1.5 hours in a Smith Synthesizer. The resulting solution issubjected to purification by reverse-phase LC-MS to yield the titlecompound. ¹H NMR 600 MHz (DMSO-d₆) δ 11.00 (s, 1H), 10.54 (s, 1H), 10.09(s, 1H), 8.69 (s, 1H), 8.50 (s, 1H), 8.30 (s, 1H), 8.28 (d, J=8.4 Hz,1H), 7.97 (d, J=6.6 Hz, 1H), 7.79 (t, J=8.4 Hz 1H), 7.64 (d, J=8.4 Hz,2H), 7.55 (s, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.28 (m, 3H), 7.06 (s, 1H),6.95 (s, 1H), 4.03 (d, J=12.6 Hz, 2H), 4.03 (d, J=12.6 Hz, 2H), 3.69 (t,J=12.6 Hz, 2H), 3.52 (d, J=12.0 Hz, 2H), 3.36 (t, J=7.8 Hz, 2H), 3.13(br, 2H), 2.98 (t, J=7.8 Hz, 2H), 2.33 (s, 3H); MS m/z 643.4 (M+1).

Example 2N-{3-[1-(6-Cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzamide

N-(3-Amino-4-methyl-phenyl)-benzamide

To a solution of 4-methyl-3-nitro-aniline (15.86 g, 104 mmol), pyridine(17.0 mL, 208 mmol) in CH₂Cl₂ (150 mL) at 0° C. was added benzoylchloride (13.30 mL, 114 mmol) dropwise. After stirring for 2 h at roomtemperature, the reaction mixture was concentrated. The residue waswashed with saturated sodium carbonate solution, water then ethyl etherto afford the desired nitro compound, which was used in the next stepwithout any further purification. ¹H NMR 600 MHz (Acetone-d₆) δ 9.85 (s,1H), 8.61 (s, 1H), 8.05-8.02 (m, 3H), 7.60 (t, 1H, J=7.2 Hz), 7.53 (t,2H, J=7.2 Hz), 7.46 (d, 1H, J=7.8 Hz), 2.54 (s, 3H); MS m/z 257.3 (M+1).

The nitro compound was dissolved in ethanol (250 mL). Afterhydrogenation on palladium (10 wt % on activated carbon, wet, Degussatype, 5 g) using Parr Shaker, 20-30 psi H₂, 16 h, the reaction mixturewas filtered through a pad of celite and washed with ethanol. Thecombined filtrate and washings were concentrated to afford the titlecompound N-(3-Amino-4-methyl-phenyl)-benzamide (22.43 g, 95% over twosteps), which was used for next reaction without any furtherpurification.

¹H NMR 600 MHz (Acetone-d₆) δ 9.40 (s, 0.4H), 9.23 (s, 0.6H), 7.96 (t,2H, J=7.8 Hz), 7.55-7.52 (m, 1H), 7.49 (d, 1H, J=7.2 Hz), 7.47 (d, 1H,J=7.2 Hz), 7.37 (d, 0.4; H, J=8.4 Hz), 7.31 (s, 0.6H), 7.17 (s, 0.4H),7.11 (d, 0.4H, J=8.4 Hz), 7.95 (d, 0.6H, J=8.4 Hz), 7.91 (d, 0.6H, J=8.4Hz), 4.44 (br, s, 1.2H), 2.90 (br, s, 0.8H), 2.11 (s, 1.8H), 1.98 (s,1.2H); MS m/z 227.3 (M+1).

N-[3-(1H-Imidazol-2-ylamino)-4-methyl-phenyl]-benzamide

A mixture of N-(2,2-diethoxyethyl)carbodiimide (10.38 g, 65.6 mmol),3-amino-4-methyl-phenyl]-benzamide (7.42 g, 32.8 mmol), methanesulfonicacid (3.20 mL, 49.3 mmol) in ethanol (200 mL) was heated at reflux for19 h. The reaction mixture was concentrated (No purification was pursuedin this step). The residue was dissolved in HCl solution (6N, 30 mL).After stirring for overnight, the reaction mixture was neutralized with25% NaOH solution at 0° C. to pH=6, then basified with saturated sodiumcarbonate solution to pH=11. The mixture was stirred for 30 minutes, andextracted with ethanol in CH₂Cl₂ (100 mL), then 10% ethanol in CH₂Cl₂(2×100 mL). The combined organic layers were dried over Na₂SO₄,filtered, concentrated and dried under vacuum. The residue wastriturated in CH₂Cl₂ (50 mL). The solid was collected by filtration andwashed with CH₂Cl₂, dried to afford the title compoundN-[3-(1H-imidazol-2-ylamino)-4-methyl-phenyl]-benzamide as a white solid(4.80 g, 50%). ¹H NMR 600 MHz (DMSO-d₆) δ 10.79 (s, 1H), 10.11 (s, 1H),8.00 (d, 1H, J=2.4 Hz), 7.94 (d, 2H, J=7.2 Hz), 7.60 (s, 1H), 7.56 (t,1H, J=7.2 Hz), 7.49 (t, 2H, J=7.2 Hz), 7.25 (dd, 1H, J=2.4, 8.4 Hz),7.04 (d, 1H, J=7.8 Hz), 6.80 (br, s, 1H), 6.65 (br, s, 1H), 2.20 (s,3H), MS m/z 293.4 (M+1).

N-{3-[1-(6-chloro-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-benzamide

A mixture of N-[3-(1H-imidazol-2-ylamino)-4-methyl-phenyl]-3-benzamide(3.41 g, 11.7 mmol), 4,6-dichloropyrimidine (5.20 g, 34.9 mmol),N,N-diisopropylethyl amine (6.10 mL, 35.0 mmol) in 2-butanol (150 mL)was heated at 100° C. After 16 h, the reaction mixture was concentrated.The residue was washed with saturated sodium carbonate, water, ethylacetate, dried to afford the title compound (2.65 g, 56%), the ethylacetate filtrate was condensed, flash chromatography (silica gel,eluting with methanol in dichloromethane from 1% to 5%, gradient) toafford an additional portion of the title compound (500 mg, 10%). ¹H NMR600 MHz (DMSO-d₆) δ 10.66 (s, 1H), 10.26 (s, 1H), 9.08 (s, 1H), 8.80 (s,1H), 8.16 (s, 1H), 7.98 (d, 2H, J=7.2 Hz), 7.82 (m, 1H), 7.58 (t, 1H),J=7.8 Hz), 7.52 (t, 2H, J=7.8 Hz), 7.39 (d, 1H, J=8.4 Hz), 7.18 (d, 1H,J=8.4 Hz), 6.93 (m, 1H), 2.36 (s, 3H); MS m/z 405.1 (M+1).

N-{3-[1-(6-Cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-benzamide

A mixture ofN-{3-[1-(6-chloro-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-benzamide(2.65 g, 6.55 mmol), cyclopropylamine (8.8 mL, 124.43 mmol) in2-propanol (30 mL) was heated at 65° C. for 16 h. The reaction mixturewas then cooled down to room temperature and concentrated. The residueyellow solid was washed with water, dried under vacuum to afford thetitle compound. The obtained crude title compound was directly used forthe next step reaction without any further purification. ¹H NMR 600 MHz(DMSO-d₆) δ 11.13 (bs, 1H), 10.24 (s, 1H), 8.77 (s, 1H), 8.48 (bs, 1H),8.10 (bs, 1H), 7.98 (d, 2H, J=6.0 Hz), 7.71 (bs, 1H), 7.57 (s, 1H), 7.52(s, 2H), 7.34 (d, 1H, J=6.6 Hz), 7.15 (d, 1H, J=6.6 Hz), 6.88 (s, 1H),6.74 (bs, 1H), 2.61 (bs, 1H), 2.33 (s, 3H), 0.82 (s, 2H), 0.53 (s, 2H);MS m/z 426.5 (M+1).

N-3-[1-(6-Cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-yl]-4-methyl-benzene-1,3-diamine

The crude product ofN-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-benzamidewas dissolved in aqueous HCl solution (6 N, 50 mL) and heated at 105° C.for 6 hours. The reaction mixture was then cooled down to roomtemperature. The white precipitate was filtered off and washed withwater. The combined filtrate solution was concentrated to viscous oil.Addition of saturated sodium carbonate aqueous solution to the oilcrushed out the title compound¹ as a yellow solid, which was collectedby filtration, washed with water and air dried (1.6 g, 74% over twosteps). ¹H NMR 600 MHz (DMSO-d₆) δ 10.91 (bs, 1H), 8.44 (bs, 1H), 8.06(bs, 1H), 7.84 (s, 1H), 7.64 (bs, 1H), 6.84 (s, 1H), 6.80 (d, 1H, J=7.8Hz), 6.70 (bs, 1 H), 6.08 (d, 1H, J=8.4 Hz), 4.82 (bs, 2H), 2.61 (bs,1H), 2.18 (s, 3H), 0.81 (s, 2H) 0.52 (s, 2H); MS m/z 322.4 (M+1).

N-{3-[1-(6-Cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzamide

To a solution ofN-3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-yl]-4-methyl-benzene-1,3-diamine(1.38 g, 4.28 mmol),3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzoic acid (1.18 g, 4.37mmol) and DIPEA (3 mL, 17.2 mmol) in DMF (20 mL), was added HATU (1.68g, 4.42 mmol) as solid. The reaction mixture was stirred at roomtemperature for 1 hour. The solvent was evaporated and the residue oilwas treated with saturated sodium bicarbonate aqueous solution. Theprecipitated off white solid was collected by filtration and washed withwater. The solid was then slurried in methanol at 50° C. for 30 min. Thesolid was collected by filtration, washed with MeOH, dried under vacuumto afford the title compound (2.14 g, 87%). ¹H NMR 400 MHz (DMSO-d₆) δ10.21 (bs, 1H), 10.52 (s, 1H), 8.78 (s, 1H), 8.54-8.44 (m, 2H), 8.42 (s,1H), 8.23 (s, 1H), 8.19 (s, 1H), 8.11 (bs, 1H), 7.72 (s, 2H), 7.40 (dd,1H, J=8.0 Hz, 1.2 Hz), 7.20 (d, 1H, J=8.4 Hz), 6.89 (d, 1H, J=1.2 Hz),6.74 (bs, 1H), 2.66 (bs, 1H), 2.35 (s, 3H), 2.19 (s, 3H), 0.82 (bs, 2H),0.53 (bs, 2H); MS m/z 574.2 (M+1).

Example 3 Synthesis of3-[1-(6-Cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-N-[4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-4-methyl-benzamide

4-Chloro-6-(2-chloro-imidazol-1-yl)-pyrimidine

2-Chloro-1H-imidazole (2.0 g, 20 mmol), 4,6-dichloropyrimidine (6 g, 40mmol) and DIEA (10.4 ml, 60 mmol) were mixed in 40 mL butanol andrefluxed at 120° C. for 24 hours. The solvent was removed by rotaryevaporation. The crude product was purified by flash chromatography onsilica gel (0% EtOAc/hexanes to 20% EtOAc/hexanes gradient), affordedthe title compound (2.6 g, 62% yield) as yellow solid. R_(f)=0.25 (20%EtOAc/hexanes); ¹H NMR 400 MHz (DMSO-d₆) δ 9.13 (s, 1H), 8.17 (s, 1H),7.94 (d, 1H), 7.17 (d, 1 H); MS m/z 215.4 (M+1).

[6-(2-Chloro-imidazol-1-yl)-pyrimidin-4-yl]-cyclopropyl-amine

4-Chloro-6-(2-chloro-imidazol-1-yl)-pyrimidine (0.85 g, 4 mmol) andcyclopropylamine (1.4 mL, 20 mmol) were mixed in 10 mL methanol andstirred at 50° C. for 12 hours. After reaction was complete, the solventwas removed by rotary evaporation. The crude product was washed withwater and taken to dryness to give the title compound (0.84 g, 90%); ¹HNMR 400 MHz (DMSO-d₆) δ 8.45 (s, 1H), 8.17 (d, 1H), 7.75 (s, 1 H), 7.08(s, 1H), 6.80 (d, 1H), 3.34 (s, 1H), 0.78 (br, 2H), 0.52 (br, 2H); MSm/z 236.4 (M+1).

Into a solution of4-(4-Ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (3.0 g,1.04 mmol, 1.0 eq.) in dichloromethane (5.2 ml) was addeddiisopropylethyl amine (2.00 ml, 1.14 mmol, 1.1 eq.). The solution wascooled to 0° C., after which 4-Methyl-3-nitrobenzoylchloride (2.13 g,1.07 mmol, 1.03 eq.) was added in portions into the reaction mixturewhich was further equilibrated for 30 minutes. The reaction mixture wasthen partitioned between dichloromethane and saturated sodium carbonatesolution. The organic layer was separated and the aqueous layer wasextracted with dichloromethane. The combined organic extracts werewashed with water, brine, dried over Na₂SO₄, filtered and concentratedto afford the desired product (4.58 g, 98%). The desired compound wasused in the next step without further purification.

Into a solutionN-[4-(4-Ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-4-methyl-3-nitro-benzamide(4.5 g, 1.00 mmol, 1.0 eq.) in MeOH (50 ml) was added Raney Nickel (0.45g, 10 wt %). The suspension was stirred under hydrogen atmosphere (1atm) for 24 hours. At the end of reaction as indicated by HPLC, thereaction mass was filtered over celite and the filtrate was concentratedunder reduced pressure to yield the desired product (4.1 g, 97%) ¹H NMR400 MHz (DMSO-d₆) δ 10.24 (s, 1H), 8.18 (s, 1H), 8.02 (d, J=8.0 Hz, 1H),7.66 (d, J=8.8 Hz, 1H, 7.16 (s, 1H), 7.13 (m, 2H), 5.1 (s, 2H), 3.55 (s,2H), 2.37 (m, 10H) 2.11 (s, 3H), 1.05 (t, 3H).

3-[1-(6-Cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-N-[4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-4-methyl-benzamide

A mixture of[6-(2-chloro-imidazol-1-yl)-pyrimidin-4-yl]-cyclopropyl-amine (2.24 g,9.53 mmol), xxxx (2.00 g, 4.76 mmol) and MeSO₃H (930 uL, 14.3 mol) in1,3-dimethyl-imidazolidin-2-one (4 mL) was heated at 90° C. in a sealedtube. After overnight, the reaction mixture was cooled to roomtemperature and diluted with CHCl₃ and washed with saturated aqueousNaHCO₃ solution. The organic layer was dried over Na₂SO₄ andconcentrated. The residue was dissolved in CHCl₃ and purified by columnchromatography (EtOAc/Hex/MeOH=9/3/1) to give the product as a whitepowder which was recrystallized from CHCl₃/MeOH to afford the titlecompound (1.15 g, 39% yield). ¹H NMR 400 MHz (DMSO-d₆) δ 11.29 (bs, 1H),10.42 (s, 1H), 9.10 (s, 1H), 8.50 (bs, 1H), 8.23 (bs, 1H), 8.08 (bs,1H), 8.04 (d, 1H, J=9.6 Hz), 7.69 (d, 1H, J=8.0 Hz), 7.71-7.69 (bs, 1H),7.46 (d, 1H, J=7.6 Hz), 7.36 (d, 1H, J=7.2 Hz), 6.91 (s, 1H), 6.75 (bs,1H), 3.56 (s, 2H), 2.65 (br, 1H), 2.43 (s, 1H), 2.43-2.33 (m, 10H), 0.98(t, 3H, J=6.8 Hz), 0.82 (bs, 2H), 0.53 (bs, 2H); MS m/z 620.3 (M+1).

By repeating the procedures described in the above examples, usingappropriate starting materials, the following compounds of Formula I, asidentified in Table 1, are obtained.

TABLE 1 Com- Physical Data pound ¹H NMR 400 MHz (DMSO- Number Structured₆) and/or MS (m/z) 3

¹H NMR 600 MHz (DMSO- d₆)δ10.09(bs, 1H), 10.54(s, 1H), 9.94(bs, 1H),8.58(bs, 1H), 8.47(bs, 1H), 8.41(s, 1H), 8.28 (d, J = 8.2 Hz, 1H),8.05(bs, 0.5H), 7.97(d, J = 8.2 Hz, 1H), 7.79(d, J = 8.2 Hz, 1H),7.58(bs, 0.5H), 7.49(d, J = 7.2 Hz, 1H), 7.28(d, J = 8.2 Hz, 1H),7.06(s, 1H), 6.77(s, 1H), 4.08-3.92(m, 2H), 3.84-3.64 (m, 4H),3.60-3.48(m, 2H), 3.40-3.28(m, 2H), 3.24-3.08(m, 2H), 2.31(s, 3H); MSm/z 567.4 (M + 1). 4

¹H NMR 600 MHz (DMSO- d₆)δ11.33(bs, 1H), 10.56(s, 1H), 8.48(bs, 1H),8.30(s, 1H), 8.27(d, J = 7.2 Hz, 2H), 7.98(d, J = 7.2 Hz, 2H), 7.80(t, J= 8.2 Hz, 1H), 7.58(d, J = 7.2 Hz, 1H), 7.33(d, J = 7.2 Hz, 1H),7.15(bs, 1H), 6.88(bs, 1H), 2.30(s, 3H), 0.84(bs, 2H), 0.55 (bs, 2H); MSm/z 494.4 (M + 1). 5

¹H NMR 600 MHz (DMSO- d₆)δ 11.42(bs, 0.5H), 11.14(bs, 0.5H), 10.56(s,1H), 8.54(bs, 0.5H), 8.43(bs, 0.5H), 8.30(s, 1H), 8.27(d, J = 8.2 Hz,1H), 7.98(d, J = 8.2 Hz, 1H), 7.96- 7.84(m, 1H), 7.79(t, J = 7.2 Hz,1H), 7.72-7.60(m, 1H), 7.58(d, J = 7.2 Hz, 1H), 7.33(d, J = 8.2 Hz, 1H),7.13(s, 1H), 6.69(s, 1H), 2.89(d, J = 16.4 Hz, 3H), 2.29(s, 3H); MS468.4 m/z (M + 1). 6

¹H NMR 600 MHz (DMSO- d₆)δ 11.40(bs, 0.5H), 11.12(bs, 0.5H), 10.56(s,1H), 8.52(bs, 0.5H), 8.43(bs, 0.5H), 8.30(s, 1H), 8.27(d, J = 8.2 Hz,1H), 8.21(bs, 1H), 7.98(d, J = 8.2 Hz, 1H), 7.90(bs, 1H), 7.80(t, J =8.2 Hz, 1H), 7.64(bs, 1H), 7.59(d, J = 7.2 Hz, 1H), 7.33(d, J = 8.2 Hz,1H), 7.20- 7.08(m, 1H), 6.80-6.68(m, 1H), 3.44-3.32(m, 4H), 3.30-3.22(m,2H), 2.29(s, 3H), 2.22(t, J = 7.2 Hz, 2H), 1.98-1.88(m, 2H),1.78-1.70(m, 2H); MS m/z 579.4 (M + 1). 7

¹H NMR 600 MHz (DMSO- d₆)δ 11.03(s, 1H), 10.56(s, 1H), 9.93(s, 1H),8.64(s, 1H), 8.30(s, 1H), 8.27(d, J = 8.2 Hz, 1H), 7.98(d, J = 8.2 Hz,1H), 7.79(t, J = 8.2 Hz, 1H), 7.66(s, 1H), 7.58(d, J = 8.2 Hz, 1H),7.33(d, J = 8.2 Hz, 1H), 7.29(s, 1H), 7.13(s, 1H), 6.97(d, J = 8.2 Hz,1H), 6.93(d, J = 8.2 Hz, 1H), 6.86(s, 1H), 6.03(s, 2H), 2.30 (s, 3H); MSm/z 574.4 (M + 1). 8

MS m/z 594.5 (M + 1). 9

¹H NMR 400 MHz (DMSO- d₆)δ11.81(bs, 1H), 8.60-8.44(m, 1H), 8.19(bs, 1H),7.84(bs, 1H), 7.52(d, J = 8.2 Hz, 1H), 7.36(t, J = 8.2 Hz, 1H), 7.06-6.96(m, 2H), 6.80(bs, 1H), 0.83(bs, 2H), 0.53(bs, 2H); MS m/z 327.10(M + 1). 10

MS m/z 393.12 (M + 1). 11

¹H NMR 400 MHz (DMSO- d₆)δ11.58(s, 1H), 9.99(s, 1H), 8.71(s, 1H),8.53(bs, 1H), 7.60-7.48(m, 4H), 7.40-7.28 (m, 2H), 7.10-7.04(m, 2H),7.04-7.00(m, 1H), 6.87(s, 1H), 4.72(q, J = 6.8 Hz, 1H), 1.34(d, J = 6.2Hz, 3H); MS m/z 407.13 (M + 1). 12

MS m/z 475.19 (M + 1). 13

MS m/z 447.26 (M + 1). 14

¹H NMR 400 MHz (DMSO- d₆)δ11.57(s, 1H), 10.02(s, 2H), 8.70(s, 1H),7.93(s, 1H), 7.55-7.50(m, 2H), 7.42-7.32 (m, 2H), 7.28(t, J = 8.2 Hz,1H), 7.24-7.18(m, 1H), 7.06- 7.00(m, 2H), 6.92(s, 1H), 2.06(s, 3H); MSm/z 420.13 (M + 1). 15

MS m/z 412.16 (M + 1). 16

MS m/z 407.05 (M + 1). 17

MS m/z 364.10 (M + 1). 18

MS m/z 531.10 (M + 1). 19

MS m/z 378.10 (M + 1). 20

¹H NMR 400 MHz (DMSO- d₆)δ10.99(s, 1H), 10.57(s, 1H), 10.51(s, 1H),9.02(d, J = 2.0 Hz, 1H), 8.79(s, 1H), 8.41 (d, J = 4.8 Hz, 1H), 8.37(s,1H), 8.33-8.25(m, 3H), 7.98(d, J = 8.2 Hz, 1H), 7.79(t, J = 8.2 Hz, 1H),7.67(d, J = 2.7 Hz, 1H), 7.63(dd, J = 8.2, 4.8 Hz, 1H), 7.54(dd, J =8.2, 1.4 Hz, 1H), 7.32(d, J = 8.2 Hz, 1H), 7.13 (d, J = 2.0 Hz, 1H),7.07(s, 1H), 2.32(s, 3H); MS m/z 545.20 (M + 1). 21

MS m/z 578.20 (M + 1). 22

¹H NMR 600 MHz (DMSO- d₆)δ11.28(bs, 1H), 10.44(s, 1H), 9.91(bs, 1H),8.48(bs, 1H), 8.40(bs, 1H), 8.22(bs, 1H), 7.89(bs, 1H), 7.79(s, 1H),7.75(s, 1H), 751(s, 1H), 7.48 (d, J = 7.2 Hz, 1H), 7.28(d, J = 8.2 Hz,1H), 7.06(s, 1H), 6.84(bs, 1H), 4.16-4.04(m, 2H), 3.60-3.44(m, 2H), ),3.24-3.04 (m, 4H), 2.89(s, 3H), 2.31(s, 3H), 0.84(s, 2H), 0.54(s, 2H);MS m/z 591.30 (M + 1). 23

¹H NMR 600 MHz (DMSO- d₆)δ11.29(bs, 1H), 10.45(s, 1H), 9.73(bs, 1H),8.48(bs, 1H), 8.38(bs, 1H), 8.23(bs, 1H), 7.89(bs, 1H), 7.78(s, 1H),7.75(s, 1H), 7.52(s, 1H), 7.49 (d, J = 7.2 Hz, 1H), 7.29(d, J = 8.2 Hz,1H), 7.07(s, 1H), 6.84(bs, 1H), 4.18-4.06(m, 2H), 3.68-3.56(m, 2H),3.28-3.18 (m, 2H), 3.18-3.08(m, 4H), 2.31(s, 3H), 1.27(t, J = 8.2 Hz,3H), 0.84(s, 2H), 0.54(s, 2H); MS m/z 605.30 (M + 1). 24

¹H NMR 600 MHz (DMSO- d₆)δ11.32(bs, 1H), 10.47(s, 1H), 8.47(bs, 1H),8.36-8.12(m, 4H), 7.98(bs, 1H), 7.65(d, J = 8.2 Hz, 1H), 7.58(d, J = 8.2Hz, 1H), 7.32(d, J = 8.2 Hz, 1H), 7.16(bs, 1H), 6.89(bs, 1H),3.76-3.70(m, 4H), 2.98-2.94 (m, 4H), 2.28(s, 3H), 0.84(s, 2H), 0.55(s,2H); MS m/z 578.30 (M + 1). 25

¹H NMR 600 MHz (DMSO- d₆)δ11.30(bs, 1H), 10.55(s, 1H), 9.46(bs, 1H),8.48(bs, 1H), 8.40-8.16(m, 4H), 7.93(d, J = 8.2 Hz, 1H), 7.53(d, J = 8.2Hz, 1H), 7.30(d, J = 8.2 Hz, 1H), 7.09(bs, 1H), 6.85(bs, 1H), 3.80(s,2H), 3.52-3.40(m, 2H), 3.20-3.12(m, 2H), 3.08-2.96 (m, 2H), 2.96-2.88(m,2H), 2.48-2.40(m, 2H), 2.30(s, 3H), 1.22(t, J = 7.2 Hz, 3H), 0.84(s,2H), 0.54(s, 2H); MS m/z 619.30 (M + 1). 26

¹H NMR 600 MHz (DMSO- d₆)δ11.31(bs, 1H), 10.55(s, 1H), 9.67(bs, 1H),8.48(bs, 1H), 8.40-8.20(m, 4H), 7.93(d, J = 8.2 Hz, 1H), 7.54(d, J = 7.2Hz, 1H), 7.31(d, J = 8.2 Hz, 1H), 7.11(s, 1H), 6.86(bs, 1H), 3.79(s,2H), 3.46-3.38(m, 2H), 3.12-3.02(m, 2H), 2.96-2.88 (m, 2H), 2.82(s, 3H),2.46-2.36 (m, 2H), 2.30(s, 3H), 0.84(s, 2H), 0.54(s, 2H); MS m/z 605.30(M + 1). 27

¹H NMR 400 MHz (DMSO-d₆) (Free base) δ11.21(bs, 1H), 10.53(s, 1H),8.78(s, 1H), 8.56-8.44(m, 3H), 8.24(s, 1H), 8.21(s, 1H), 8.11(bs, 1H),7.76 (s, 1H), 7.73(bs, 1H), 7.41(dd, J = 8.2, 2.0 Hz, 1H), 7.20(d, J =8.2 Hz, 1H), 6.89(s, 1H), 6.74(bs, 1H), 2.35(s, 3H), 2.21 (s, 3H),0.82(s, 2H), 0.53(s, 2H); MS m/z 574.30 (M + 1). 29

MS m/z 547.20 (M + 1). 30

¹H NMR 600 MHz (DMSO-d₆) δ11.42(bs, 0.5H), 11.13(bs, 0.5H), 10.47(s,1H), 8.54(s, 0.5H), 8.43(s, 0.5H), 8.25(s, 1H), 8.24(s, 1H),8.22-8.12(m, 1H), 8.02(bs, 1H), 7.88(bs, 1H), 7.65(d, J = 8.2 Hz, 1H),7.58(d, J = 8.2 Hz, 1H), 7.32(d, J = 8.2 Hz, 1H), 7.15(bs, 1H), 6.71(s,1H), 3.74(t, J = 5.1 Hz, 4H), 2.96(t, J = 5.1 Hz, 4H), 2.89(d, J = 18.4Hz, 1H), 2.28 (s, 3H); MS m/z 552.30 (M + 1). 31

¹H NMR 600 MHz (DMSO-d₆) δ11.39(bs, 0.5H), 11.13(bs, 0.5H), 10.46(s,1H), 8.54(bs, 0.5H), 8.43(s, 0.5H), 8.34(bs, 1H), 7.85(s, 1H), 7.78(s,1H), 7.75(s, 1H), 7.64-7.54(m, 1H), 7.53-7.47(m, 2H), 7.29(d, J = 8.2Hz, 1H), 7.07(bs, 1H), 6.68(s, 1H), 4.18-4.04(m, 2H), 3.66-3.56(m, 2H),3.28-3.20(m, 2H), 3.20-3.08(m, 4H), 2.96- 2.84(m, 3H), 2.31(s, 3H),1.27(t, J = 8.2 Hz, 3H); MS m/z 579.30 (M + 1). 32

¹H NMR 600 MHz (DMSO-d₆) δ11.39(bs, 0.5H), 11.13(bs, 0.5H), 10.45(s,1H), 8.53(bs, 0.5H), 8.43(s, 0.5H), 8.33(bs, 1H), 7.85(s, 1H), 7.79(s,1H), 7.74(s, 1H), 7.64-7.54(m, 1H), 7.53-7.47(m, 2H), 7.29(d, J = 9.2Hz, 1H), 7.08(bs, 1H), 6.68(s, 1H), 4.16-4.04(m, 2H), 3.60-3.48(m, 2H),3.24-3.08(m, 4H), 2.96-2.84(m, 6H), 2.30(s, 3H); MS m/z 565.30 (M + 1).33

¹H NMR 600 MHz (DMSO-d₆) δ11.40(bs, 0.5H), 11.14(bs, 0.5H), 10.56(s,1H), 9.78(bs, 1H), 8.54(s, 0.5H), 8.43(bs, 0.5H), 8.30(s, 1H), 8.26(d, J= 8.2 Hz, 1H), 7.95(bs, 0.5H), 7.92(d, J = 8.2 Hz, 1H), 7.87(s, 1H),7.62(bs, 0.5H), 7.55(d, J = 8.2 Hz, 1H), 7.31(d, J = 8.2 Hz, 1H),7.10(s, 1H), 6.69(s, 1H), 3.79(s, 2H), 3.42(d, J = 11.3 Hz, 2H), 3.07(d,J = 11.3 Hz, 2H), 2.96-2.84(m, 2H), 2.82(s, 3H), 2.43(d, J = 11.3 Hz,2H), 2.29(s, 3H); MS m/z 579.30 (M + 1). 34

¹H NMR 600 MHz (DMSO-d₆) δ11.41(bs, 0.5H), 11.14(bs, 0.5H), 10.56(s,1H), 9.55(bs, 1H), 8.54(bs, 0.5H), 8.43(bs, 0.5H), 8.30(s, 1H), 8.26(d,J = 8.2 Hz, 1H), 7.98(bs, 0.5H), 7.93(d, J = 8.2 Hz, 1H), 7.88(s, 1H),7.62(bs, 0.5H), 7.55(d, J = 8.2 Hz, 1H), 7.31(d, J = 8.2 Hz, 1H),7.11(s, 1H), 6.70(s, 1H), 3.80(s, 2H), 3.48(d, J = 12.3 Hz, 3H), 3.16(q,J = 7.2 Hz, 2H), 3.06-2.98(m, 2H), 2.98- 2.82(m, 4H), 2.44(t, J = 11.3Hz, 2H), 2.30(s, 3H), 1.22(t, J = 7.2 Hz, 3H); MS m/z 593.30 (M + 1). 35

MS m/z 593.30 (M + 1). 36

MS m/z 567.30 (M + 1). 37

¹H NMR 400 MHz (DMSO-d₆) δ11.19(s, 1H), 10.55(s, 1H), 8.45(s, 1H),8.30(s, 2H), 8.26 (d, J = 8.8 Hz, IH), 7.93(d, J = 8.2 Hz, 1H), 7.62(s,1H), 7.54(d, J = 8.2 Hz, 1H), 7.44(s, 2H), 7.30(d, J = 8.8 Hz, 1H),7.08(s, 1H), 6.62(s, 1H), 3.80(s, 2H), 3.52-3.42(m, 2H), 3.22-3.10(m,2H), 3.08-2.92(m, 4H), 2.48-2.36(m, 2H), 2.29(s, 3H), 1.21(t, J = 7.5Hz, 3H); MS m/z 580.30 (M + 1). 38

¹H NMR 400 MHz (DMSO-d₆) δ11.19(s, 1H), 10.55(s, 1H), 8.45(s, 1H),8.30(s, 2H), 8.26 (d, J = 9.6 Hz, 1H), 7.92(d, J = 8.2 Hz, 1H), 7.62(s,1H), 7.54(d, J = 9.6 Hz, 1H), 7.43(s, 2H), 7.30(d, J = 8.2 Hz, 1H),7.08(s, 1H), 6.62(s, 1H), 3.79(s, 2H), 3.46-3.36(m, 2H), 3.12-3.10(m,2H), 2.96-2.88(m, 2H), 2.82(s, 3H), 2.46-2.34(m, 2H), 2.29(s, 3H); MSm/z 566.30 (M + 1). 39

¹H NMR 400 MHz (DMSO-d₆) δ11.20(s, 1H), 10.66(s, 1H), 9.59(s, 1H),8.60(s, 1H), 8.50- 8.40(m, 4H), 8.16(2, 1H), 7.56(s, 1H), 7.51(d, J =9.6 Hz, 1H), 7.39(s, 2H), 7.30(d, J = 8.2 Hz, 1H), 7.01(s, 1H), 6.59(s,1H), 2.35(s, 3H), 2.32 (s, 3H); MS m/z 534.20 (M + 1). 40

¹H NMR 400 MHz (DMSO-d₆) δ11.19(s, 1H), 10.47(s, 1H), 8.45(s, 1H),8.25(s, 1H), 8.18- 8.10(m, 2H), 7.70-7.63(m, 1H), 7.58(d, J = 8.8 Hz,1H), 7.51(s, 1H), 7.46(s, 2H), 7.32(d, J = 8.2 Hz, 1H), 7.14(s, 1H),6.63(s, 1H), 2.96(t, J = 4.1 Hz, 4H), 2.92(t, J = 4.1 Hz, 4H), 2.28(s,3H); MS m/z 539.20 (M + 1). 41

MS m/z 566.30 (M + 1). 42

¹H NMR 400 MHz (DMSO-d₆) δ11.18(s, 1H), 10.44(s, 1H), 8.45(s, 2H),7.78(s, 1H), 7.75(s, 2H), 7.56(d, J = 6.8 Hz, 1H), 7.51(s, 1H), 7.47(d,J = 8.2 Hz, 1H), 7.40(s, 1H), 7.27(d, J = 8.2 Hz, 1H), 7.03(s, 1H),6.60(s, 1H), 4.16-4.04(m, 2H), 3.64-3.48(m, 2H), 3.24-3.04(m, 4H),2.88(s, 3H), 2.30(s, 3H); MS m/z 552.30 (M + 1). 43

¹H NMR 400 MHz (DMSO-d₆) δ11.19(s, 1H), 10.61(s, 1H), 8.45(s, 1H),8.40-8.24(m, 3H), 8.03(d, J = 7.5 Hz, 1H), 7.63(s, 1H), 7.55(d, J = 8.2Hz, 1H), 7.44(s, 2H), 7.31(d, J = 8.2 Hz, 1H), 7.09(s, 1H), 6.63(s, 1H),3.91(s, 2H), 3.82-3.68(m, 4H), 3.20-2.80(m, 4H), 2.29(s, 3H); MS m/z553.30 (M + 1). 44

MS m/z 353.40 (M + 1). 45

¹H NMR 600 MHz (DMSO- d₆)δ11.15(bs, 1H), 10.51(s, 1H), 8.48(bs, 1H),8.30(s, 1H), 8.27 (d, J = 7.2 Hz, 1H), 8.21(bs, 1H), 7.99(d, J = 7.2 Hz,1H), 7.84(bs, 1H), 7.80(t, J = 8.2 Hz, 1H), 7.58(s, 1H), 7.21(s, 1H),7.10(bs, 1H), 6.83(bs, 1H), 3.79(s, 3H), 0.82(s, 2H), 0.53 (s, 2H); MSm/z 510.10 (M + 1). 46

¹H NMR 400 MHz (DMSO- d₆)δ11.30(s, 1H), 9.81(s, 1H), 8.63(s, 1H),7.78(s, 1H), 7.52(s, 1H), 7.46(d, J = 8.2 Hz, 1H), 7.05(s, 1H),7.02-6.96(m, 3H), 6.77(s, 1H), 6.61(dd, J = 8.2, 2.0 Hz, 1H), 3.86(s,3H), 3.78- 3.73(m, 4H), 3.72(s, 3H), 3.13- 3.07(m, 4H); MS m/z 474.30(M + 1). 47

MS m/z 474.30 (M + 1). 48

¹H NMR 400 MHz (DMSO- d₆)δ10.86(s, 1H), 9.93(s, 1H), 8.61(s, 1H),7.67(s, 1H), 7.46 (d, J = 7.5 Hz, 2H), 7.21(d, J = 1.4 Hz, 1H), 6.99(s,1H), 6.97(s, 1H), 6.88(s, 1H), 6.86(s, 2H), 3.79(s, 6H), 3.78- 3.73(m,4H), 3.67(s, 3H), 3.13- 3.07(m, 4H); MS m/z 504.30 (M + 1). 49

MS m/z 615.30 (M + 1). 50

¹H NMR 400 MHz (DMSO- d₆)δ10.86(s, 1H), 10.55(s, 1H), 9.88(s, 1H),8.62(s, 1H), 8.29(s, 1H), 8.26(d, J = 7.5 Hz, 1H), 7.99(d, J = 8.2 Hz,1H), 7.80(t, J = 8.2 Hz, 1H), 7.62(s, 1H), 7.58(s, 1H), 7.50-7.40(m,2H), 7.23(s, 1H), 7.18(s, 1H), 7.02-6.94(m, 3H), 6.86(s, 1H), 3.79(s,3H), 3.78-3.71(m, 4H), 3.12-3.05(m, 4H); MS m/z 631.30 (M + 1). 51

MS m/z 494.30 (M + 1). 52

MS m/z 538.30 (M + 1). 53

MS m/z 574.30 (M + 1). 54

¹H NMR 600 MHz (DMSO-d₆) δ11.31(bs, 1H), 10.76(s, 1H), 8.58(s, 1H),8.54(d, J = 8.2 Hz, 1H), 8.49(s, 1H), 8.44(bs, 1H), 8.24(bs, 1H),8.07(d, J = 8.2 Hz, 1H), 7.97(s, 1H), 7.91(bs, 1H), 7.84(d, J = 2.0 Hz,1H), 7.56(d, J = 7.2 Hz, 1H), 7.32 (d, J = 8.2 Hz, 1H), 7.08(s, 1H),6.86(bs, 1H), 2.64-2.60(m, 1H), 2.41(s, 3H), 2.33(s, 3H), 0.85(bs, 2H),0.55(bs, 2H); MS m/z 573.22 (M + 1). 55

MS m/z 605.28 (M + 1). 56

MS m/z 536.23 (M + 1). 57

MS m/z 591.27 (M + 1). 58

¹H NMR 600 MHz (DMSO-d₆) δ11.19(s, 1H), 10.75(s, 1H), 8.58(s, 1H),8.53(d, J = 8.2 Hz, 1H), 8.46(s, 1H), 8.06(d, J = 8.2 Hz, 1H), 7.96(s,1H), 7.84(s, 1H), 7.58(s, 1H), 7.54(d, J = 8.2 Hz, 1H), 7.40(s, 2H),7.31(d, J = 8.2 Hz, 1H), 7.05(s, 1H), 6.61(s, 2H), 2.40(s, 3H), 2.32 (s,3H); MS m/z 533.19 (M + 1). 59

¹H NMR 600 MHz (DMSO-d₆) δ11.19(s, 1H), 10.56(s, 1H), 8.46(s, 1H),8.28(s, 1H), 8.23(s, 1H), 7.93(s, 1H), 7.62(s, 1H), 7.54(d, J = 7.2 Hz,1H), 7.43(s, 2H), 7.31(d, J = 8.2 Hz, 1H), 7.08(s, 1H), 6.62(s, 1H),3.84(s, 2H), 3.52-3.42(m, 2H), 3.13(q, J = 7.2 Hz, 2H), 3.08- 3.96(m,4H), 2.30(s, 3H), 1.20(t, J = 7.2 Hz, 3H); MS m/z 579.27 (M + 1). 60

¹H NMR 600 MHz (DMSO-d₆) δ11.18(s, 1H), 10.43(s, 1H), 8.45(s, 1H),7.75(s, 1H), 7.70(s, 0.5H), 7.66(s, 1H), 7.60(s, 1H), 7.54(s, 05H),7.52-7.48(m, 1H), 7.44(s, 1H), 7.41(s, 2H), 7.29(d, J = 8.2 Hz, 1H),7.06(s, 1H), 6.62(s, 1H), 4.10-4.00(m, 1H), 3.60-3.52(m, 2H),3.40-3.30(m, 2H), 3.16- 3.06(m, 2H), 2.92-2.82(m, 2H), 2.30(s, 3H),2.20-2.10(m, 2H), 2.06-1.98(m, 2H), 1.90-1.80(m, 2H), 1.72-1.60(m, 2H);MS m/z 605.28 (M + 1). 61

¹H NMR 600 MHz (DMSO-d₆) δ11.19(s, 1H), 10.55(s, 1H), 8.66(s, 2H),8.45(s, 1H), 8.29(s, 1H), 8.26(d, J = 8.2 Hz, 1H), 7.94(d, J = 8.2 Hz,1H), 7.64(s, 1H), 7.56(d, J = 8.2 Hz, 1H), 7.44(s, 1H), 7.31(d, J = 8.2Hz, 1H), 7.10(s, 1H), 6.63(s, 1H), 3.78(s, 2H), 3.16- 3.10(m, 4H),2.66-2.60(m, 4H), 2.29(s, 3H); MS m/z 551.24 (M + 1). 62

¹H NMR 600 MHz (DMSO-d₆) δ11.31(s, 1H), 10.56(s, 1H), 8.49(bs, 1H),8.34(bs, 1H), 8.29(s, 1H), 8.23(s, 1H), 7.93(s, 1H), 7.54(d, J = 7.2 Hz,1H), 7.31(d, J = 8.2 Hz, 1H), 7.10(s, 1H), 6.86(bs, 1H), 3.84(s, 2H),3.52-3.44(m, 4H), 3.14(q, J = 7.2 Hz, 2H), 3.08-2.96(m, 4H),2.48-2.40(m, 1H), 2.31(s, 3H), 1.20(t, J = 7.2 Hz, 3H), 0.85(bs, 2H),0.55(bs, 2H); MS m/z 619.30 (M + 1). 63

¹H NMR 600 MHz (DMSO-d₆) δ11.30(bs, 1H), 10.43(s, 1H), 9.69(s, 1H),8.48(s, 1H), 8.33(s, 1H), 8.24(s, 1H), 7.92(s, 1H), 7.75(s, 1H), 7.66(s,1H), 7.56-7.48(m, 1H), 7.44(s, 1H), 7.30(d, J = 8.2 Hz, 1H), 7.09 (s,1H), 6.86(bs, 1H), 4.06(d, J = 13.3 Hz, 2H), 3.40-3.28(m, 2H),3.16-3.06(m, 2H), 2.88(t, J = 12.3 Hz, 2H), 2.64-2.58(m, 1H),2.54-2.50(m, 1H), 2.31(s, 3H), 2.15(d, J = 11.3 Hz, 2H), 2.08-1.96(m,2H), 1.90-1.80 (m, 2H), 1.72-1.62(m, 2H), 0.84(bs, 2H), 0.54(bs, 2H); MSm/z 645.32 (M + 1). 64

MS m/z 585.27 (M + 1). 65

¹H NMR 600 MHz (DMSO-d₆) δ11.30(bs, 1H), 10.55(s, 1H), 8.66(s, 1H),8.48(s, 1H), 8.29(s, 1H), 8.26(s, 1H), 8.25(s, 1H), 7.95(s, 1H), 7.94(s,1H), 7.54(d, J = 7.2 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 7.10(s, 1H),6.86(bs, 1H), 3.78(s, 2H), 3.16-3.10(m, 4H), 2.66-2.60(m, 4H),2.54-2.50(m, 1H), 2.30(s, 3H), 0.85(bs, 2H), 0.54(bs, 2H); MS m/z 591.27(M + 1). 66

MS m/z 592.25 (M + 1). 67

MS m/z 606.27 (M + 1). 68

MS m/z 552.22 (M + 1). 69

MS m/z 566.24 (M + 1). 70

MS m/z 590.22 (M + 1). 71

MS m/z 496.16 (M + 1). 72

MS m/z 532.13 (M + 1). 73

MS m/z 494.18 (M + 1). 74

MS m/z 574.22 (M + 1). 75

MS m/z 592.27 (M + 1). 76

MS m/z 552.24 (M + 1). 77

MS m/z 622.25 (M + 1). 78

MS m/z 636.29 (M + 1). 79

MS m/z 593.25 (M + 1). 80

MS m/z 553.22 (M + 1). 81

MS m/z 662.30 (M + 1). 82

MS m/z 589.23 (M + 1). 83

MS m/z 635.31 (M + 1). 84

MS m/z 428.5 (M + 1). 85

MS m/z 461.2 (M + 1). 86

MS m/z 416.4 (M + 1). 87

MS m/z 429.5 (M + 1). 88

MS m/z 416.5 (M + 1). 89

MS m/z 494.5 (M + 1). 90

MS m/z 441.5 (M + 1). 91

MS m/z 486.6 (M + 1). 92

MS m/z 693.8 (M + 1). 93

MS m/z 647.7 (M + 1). 94

MS m/z 647.7 (M + 1). 95

MS m/z 680.8 (M + 1). 96

MS m/z 428.5 (M + 1). 97

MS m/z 442.3 (M + 1). 98

MS m/z 478.5 (M + 1). 99

MS m/z 585.7 (M + 1). 100

MS m/z 486.6 (M + 1). 101

MS m/z 562.7 (M + 1). 102

MS m/z 592.6 (M + 1). 103

MS m/z 593.6 (M + 1). 104

MS m/z 486.6 (M + 1). 105

MS m/z 486.6 (M + 1). 106

MS m/z 543.7 (M + 1). 107

MS m/z 557.7 (M + 1). 108

MS m/z 488.6 (M + 1). 109

MS m/z 559.7 (M + 1). 110

MS m/z 561.7 (M + 1). 111

MS m/z 559.7 (M + 1). 112

MS m/z 551.2 (M + 1). 113

MS m/z 537.2 (M + 1). 114

MS m/z 580.3 (M + 1). 115

MS m/z 548.2 (M + 1). 116

MS m/z 552.2 (M + 1). 117

MS m/z 534.2 (M + 1). 118

MS m/z 559.2 (M + 1). 119

MS m/z 545.2 (M + 1). 120

MS m/z 545.2 (M + 1). 121

1H NMR 400 MHz (DMSO- d6) 11.17(br, 1H), 10.36(s, 1H), 8.75(s, 1H),8.49(s, 1H), 8.11(br, 1H), 7.75(s, 1H), 7.66(s, 1H), 7.36(br, 1H),7.32(d, 1H), 7.17(d, 1H), 6.88 (s, 1H), 6.73(br, 1H), 3.33(m, 4H),2.50(m, 4H), 2.34(s, 3H), 2.26(s, 3H), 1.99(s, 1H), 0.82 (m, 2H),0.53(m, 2H); MS m/z 592.3 (M + 1). 122

1H NMR 400 MHz (DMSO- d6) 11.14(br, 1H), 10.36(s, 1H), 8.75(s, 1H),8.50(s, 1H), 8.08(br, 1H), 7.74(br, 2H), 7.65(b, 2H), 7.35(s, 1H),7.32(d, 1H), 7.17(d, 1H), 6.89 (s, 1H), 4.48(br, 1H), 3.56(br, 1H),3.34(m, 6H), 2.60, 2.50 (m, 6H), 2.34(s, 3H), 0.83(m, 2H), 0.53(m, 2H);MS m/z 622.3 (M + 1). 123

MS m/z 578.3 (M + 1). 124

MS m/z 446.2 (M + 1) 125

MS m/z 430.2 (M + 1) 126

MS m/z 426.2 (M + 1) 127

MS m/z 430.2 (M + 1) 128

MS m/z 426.2 (M + 1) 129

MS m/z 613.3 (M + 1) 130

MS m/z 597.3 (M + 1) 131

MS m/z 593.3 (M + 1) 132

MS m/z 594.3 (M + 1) 133

MS m/z 578.3 (M + 1) 134

MS m/z 574.3 (M + 1) 135

MS m/z 577.3 (M + 1) 136

MS m/z 574.3 (M + 1) 137

MS m/z 442.3 (M + 1) 138

MS m/z 530.3 (M + 1) 139

MS m/z 530.3 (M + 1) 140

MS m/z 541.3 (M + 1) 141

MS m/z 537.3 (M + 1) 142

MS m/z 557.3 (M + 1) 143

MS m/z 611.3 (M + 1) 144

MS m/z 657.3 (M + 1) 145

MS m/z 643.3 (M + 1) 146

MS m/z 565.3 (M + 1) 147

MS m/z 643.3 (M + 1) 148

MS m/z 545.3 (M + 1) 149

MS m/z 559.3 (M + 1) 150

MS m/z 574.3 (M + 1) 151

MS m/z 545.3 (M + 1) 152

MS m/z 556.3 (M + 1) 153

MS m/z 528.3 (M + 1) 154

MS m/z 601.3 (M + 1) 155

MS m/z 559.3 (M + 1) 156

MS m/z 525.3 (M + 1) 157

MS m/z 581.3 (M + 1) 158

MS m/z 512.3 (M + 1) 159

MS m/z 565.3 (M + 1) 160

MS m/z 531.3 (M + 1) 161

MS m/z 439.3 (M + 1) 162

MS m/z 439.3 (M + 1) 163

MS m/z 468.3 (M + 1) 164

MS m/z 468.3 (M + 1) 165

MS m/z 567.3 (M + 1) 166

MS m/z 567.3 (M + 1) 167

MS m/z 548.3 (M + 1) 168

MS m/z 539.3 (M + 1) 169

MS m/z 496.3 (M + 1) 170

MS m/z 534.3 (M + 1) 171

MS m/z 594.3 (M + 1) 172

MS m/z 588.3 (M + 1) 173

MS m/z 630.3 (M + 1) 174

MS m/z 546.3 (M + 1) 175

MS m/z 561.3 (M + 1) 176

MS m/z 524.3 (M + 1) 177

MS m/z 551.3 (M + 1) 178

MS m/z 548.3 (M + 1) 179

MS m/z 644.3 (M + 1) 180

MS m/z 545.3 (M + 1) 181

MS m/z 545.3 (M + 1) 182

MS m/z 607.3 (M + 1) 183

MS m/z 551.3 (M + 1) 184

MS m/z 545.3 (M + 1) 185

MS m/z 560.3 (M + 1) 186

MS m/z 600.3 (M + 1) 187

MS m/z 562.3 (M + 1) 188

MS m/z 532.3 (M + 1) 189

MS m/z 573.3 (M + 1) 190

MS m/z 567.2 (M + 1) 191

MS m/z 552.2 (M + 1) 192

MS m/z 601.2 (M + 1) 193

MS m/z 586.2 (M + 1) 194

MS m/z 584.4 (M + 1) 195

MS m/z 571.3 (M + 1) 196

MS m/z 562.3 (M + 1) 197

MS m/z 547.3 (M + 1) 198

MS m/z 544.3 (M + 1) 199

MS m/z 484.3 (M + 1) 200

MS m/z 559.3 (M + 1) 201

MS m/z 566.2 (M + 1) 202

MS m/z 495.2 (M + 1) 203

MS m/z 481.2 (M + 1)

Assays

Compounds of the present invention are assayed to measure their capacityselectively inhibit cell proliferation of 32D cells expressing BCR-Abl(32D-p210) compared with parental 32D cells. Compounds selectivelyinhibiting the proliferation of these BCR-Abl transformed cells aretested for anti-proliferative activity on Ba/F3 cells expressing eitherwild type or the mutant forms of Bcr-abl. In addition, compounds areassayed to measure their capacity to inhibit FGFR3, b-RAF, Abl, BMX,BTK, CHK2, c-RAF, CSK, c-SRC, Fes, Flt3, IKKα, IKKβ, JNK2α2, Lck, Met,MKK4, MKK6, MST2, NEK2, p70S6K, PDGFRα, PKA, PKBα, PKD2, Rsk1, SAPK2α,SAPK2β, SAPK3, SGK, Tie2 and trkB kinases.

Inhibition of Cellular BCR-Abl Dependent Proliferation (High ThroughputMethod)

The murine cell line used is the 32D hemopoietic progenitor cell linetransformed with BCR-Abl cDNA (32D-p210). These cells are maintained inRPMI/10% fetal calf serum (RPMI/FCS) supplemented with penicillin 50μg/mL, streptomycin 50 μg/mL and L-glutamine 200 mM. Untransformed 32Dcells are similarly maintained with the addition of 15% of WEHIconditioned medium as a source of IL3.

50 μl of a 32D or 32D-p210 cells suspension are plated in Greiner 384well microplates (black) at a density of 5000 cells per well. 50 nl oftest compound (1 mM in DMSO stock solution) is added to each well(STI571 is included as a positive control). The cells are incubated for72 hours at 37° C., 5% CO₂. 10 μl of a 60% Alamar Blue solution (Tekdiagnostics) is added to each well and the cells are incubated for anadditional 24 hours. The fluorescence intensity (Excitation at 530 nm,Emission at 580 nm) is quantified using the Acquest™ system (MolecularDevices).

Inhibition of Cellular BCR-Abl Dependent Proliferation

32D-p210 cells are plated into 96 well TC plates at a density of 15,000cells per well. 50 μL of two fold serial dilutions of the test compound(C_(max) is 40 μM) are added to each well (STI571 is included as apositive control). After incubating the cells for 48 hours at 37° C., 5%CO₂, 15 μL of MTT (Promega) is added to each well and the cells areincubated for an additional 5 hours. The optical density at 570 nm isquantified spectrophotometrically and IC₅₀ values, the concentration ofcompound required for 50% inhibition, determined from a dose responsecurve.

Effect on Cell Cycle Distribution

32D and 32D-p210 cells are plated into 6 well TC plates at 2.5×10⁶ cellsper well in 5 ml of medium and test compound at 1 or 10 μM is added(STI571 is included as a control). The cells are then incubated for 24or 48 hours at 37° C., 5% CO₂. 2 ml of cell suspension is washed withPBS, fixed in 70% EtOH for 1 hour and treated with PBS/EDTA/RNase A for30 minutes. Propidium iodide (Cf=10 μg/ml) is added and the fluorescenceintensity is quantified by flow cytometry on the FACScalibur™ system (BDBiosciences). Test compounds of the present invention demonstrate anapoptotic effect on the 32D-p210 cells but do not induce apoptosis inthe 32D parental cells.

Effect on Cellular BCR-Abl Autophosphorylation

BCR-Abl autophosphorylation is quantified with capture Elisa using ac-abl specific capture antibody and an antiphosphotyrosine antibody.32D-p210 cells are plated in 96 well TC plates at 2×10⁵ cells per wellin 50 μL of medium. 50 μL of two fold serial dilutions of test compounds(C_(max) is 10 μM) are added to each well (STI571 is included as apositive control). The cells are incubated for 90 minutes at 37° C., 5%CO₂. The cells are then treated for 1 hour on ice with 150 μL of lysisbuffer (50 mM Tris-HCl, pH 7.4, 150 mM NaCl, 5 mM EDTA, 1 mM EGTA and 1%NP-40) containing protease and phosphatase inhibitors. 50 μL of celllysate is added to 96 well optiplates previously coated with anti-ablspecific antibody and blocked. The plates are incubated for 4 hours at4° C. After washing with TBS-Tween 20 buffer, 50 μL ofalkaline-phosphatase conjugated anti-phosphotyrosine antibody is addedand the plate is further incubated overnight at 4° C. After washing withTBS-Tween 20 buffer, 90 μL of a luminescent substrate are added and theluminescence is quantified using the Acquest™ system (MolecularDevices). Test compounds of the invention that inhibit the proliferationof the BCR-Abl expressing cells, inhibit the cellular BCR-Ablautophosphorylation in a dose-dependent manner.

Effect on Proliferation of Cells Expressing Mutant Forms of Bcr-abl

Compounds of the invention are tested for their antiproliferative effecton Ba/F3 cells expressing either wild type or the mutant forms ofBCR-Abl (G250E, E255V, T3151, F317L, M351T) that confers resistance ordiminished sensitivity to STI571. The antiproliferative effect of thesecompounds on the mutant-BCR-Abl expressing cells and on the nontransformed cells were tested at 10, 3.3, 1.1 and 0.37 μM as describedabove (in media lacking IL3). The IC₅₀ values of the compounds lackingtoxicity on the untransformed cells were determined from the doseresponse curves obtained as describe above.

FGFR3 (Enzymatic Assay)

Kinase activity assay with purified FGFR3 (Upstate) is carried out in afinal volume of 10 μL containing 0.25 μg/mL of enzyme in kinase buffer(30 mM Tris-HCl pH7.5, 15 mM MgCl₂, 4.5 mM MnCl₂, 15 μM Na₃VO₄ and 50μg/mL BSA), and substrates (5 μg/mL biotin-poly-EY (Glu, Tyr) (CIS-US,Inc.) and 3 μM ATP). Two solutions are made: the first solution of 5 μlcontains the FGFR3 enzyme in kinase buffer was first dispensed into384-format ProxiPlate® (Perkin-Elmer) followed by adding 50 nL ofcompounds dissolved in DMSO, then 5 μl of second solution contains thesubstrate (poly-EY) and ATP in kinase buffer was added to each wells.The reactions are incubated at room temperature for one hour, stopped byadding 10 μL of HTRF detection mixture, which contains 30 mM Tris-HClpH7.5, 0.5 M KF, 50 mM ETDA, 0.2 mg/mL BSA, 15 μg/mL streptavidin-XL665(CIS-US, Inc.) and 150 ng/mL cryptate conjugated anti-phosphotyrosineantibody (CIS-US, Inc.). After one hour of room temperature incubationto allow for streptavidin-biotin interaction, time resolved florescentsignals are read on Analyst GT (Molecular Devices Corp.). IC₅₀ valuesare calculated by linear regression analysis of the percentageinhibition of each compound at 12 concentrations (1:3 dilution from 50μM to 0.28 nM). In this assay, compounds of the invention have an IC₅₀in the range of 10 nM to 2 μM.

FGFR3 (Cellular Assay)

Compounds of the invention are tested for their ability to inhibittransformed Ba/F3-TEL-FGFR3 cells proliferation, which is depended onFGFR3 cellular kinase activity. Ba/F3-TEL-FGFR3 are cultured up to800,000 cells/mL in suspension, with RPMI 1640 supplemented with 10%fetal bovine serum as the culture medium. Cells are dispensed into384-well format plate at 5000 cell/well in 50 μL culture medium.Compounds of the invention are dissolved and diluted in dimethylsufoxide(DMSO). Twelve points 1:3 serial dilutions are made into DMSO to createconcentrations gradient ranging typically from 10 mM to 0.05 μM. Cellsare added with 50 nL of diluted compounds and incubated for 48 hours incell culture incubator. AlamarBlue® (TREK Diagnostic Systems), which canbe used to monitor the reducing environment created by proliferatingcells, are added to cells at final concentration of 10%. Afteradditional four hours of incubation in a 37° C. cell culture incubator,fluorescence signals from reduced AlamarBlue® (Excitation at 530 nm,Emission at 580 nm) are quantified on Analyst GT (Molecular DevicesCorp.). IC₅₀ values are calculated by linear regression analysis of thepercentage inhibition of each compound at 12 concentrations.

FLT3 and PDGFRβ (Cellular Assay)

The effects of compounds of the invention on the cellular activity ofFLT3 and PDGFRβ are conducted using identical methods as described abovefor FGFR3 cellular activity, except that instead of usingBa/F3-TEL-FGFR3, Ba/F3-FLT3-ITD and Ba/F3-Tel-PDGFRβ are used,respectively.

b-Raf—Enzymatic Assay

Compounds of the invention are tested for their ability to inhibit theactivity of b-Raf. The assay is carried out in 384-well MaxiSorp plates(NUNC) with black walls and clear bottom. The substrate, IκBα is dilutedin DPBS (1:750) and 15 μl is added to each well. The plates areincubated at 4° C. overnight and washed 3 times with TBST (25 mM Tris,pH 8.0, 150 mM NaCl and 0.05% Tween-20) using the EMBLA plate washer.Plates are blocked by Superblock (15 μl/well) for 3 hours at roomtemperature, washed 3 times with TBST and pat-dried. Assay buffercontaining 20 μM ATP (10 μl) is added to each well followed by 100 nl or500 nl of compound. B-Raf is diluted in the assay buffer (1 μl into 25μl) and 10 μl of diluted b-Raf is added to each well (0.4 μg/well). Theplates are incubated at room temperature for 2.5 hours. The kinasereaction is stopped by washing the plates 6 times with TBST. Phosph-IκBα(Ser32/36) antibody is diluted in Superblock (1:10,000) and 15 μl isadded to each well. The plates are incubated at 4° C. overnight andwashed 6 times with TBST. AP-conjugated goat-anti-mouse IgG is dilutedin Superblock (1:1,500) and 15 μl is added to each well. Plates areincubated at room temperature for 1 hour and washed 6 times with TBST.15 μl of fluorescent Attophos AP substrate (Promega) is added to eachwell and plates are incubated at room temperature for 15 minutes. Platesare read on Acquest or Analyst GT using a Fluorescence Intensity Program(Excitation 455 nm, Emission 580 nm).

b-Raf—Cellular Assay

Compounds of the invention are tested in A375 cells for their ability toinhibit phosphorylation of MEK. A375 cell line (ATCC) is derived from ahuman melanoma patient and it has a V599E mutation on the B-Raf gene.The levels of phosphorylated MEK are elevated due to the mutation ofB-Raf. Sub-confluent to confluent A375 cells are incubated withcompounds for 2 hours at 37° C. in serum free medium. Cells are thenwashed once with cold PBS and lysed with the lysis buffer containing 1%Triton X100. After centrifugation, the supernatants are subjected toSDS-PAGE, and then transferred to nitrocellulose membranes. Themembranes are then subjected to western blotting with anti-phospho-MEKantibody (ser217/221) (Cell Signaling). The amount of phosphorylated MEKis monitored by the density of phospho-MEK bands on the nitrocellulosemembranes.

Upstate KinaseProfiler™—Radio-Enzymatic Filter Binding Assay

Compounds of the invention are assessed for their ability to inhibitindividual members of the kinase panel. The compounds are tested induplicates at a final concentration of 10 μM following this genericprotocol. Note that the kinase buffer composition and the substratesvary for the different kinases included in the “Upstate KinaseProfiler™”panel. Kinase buffer (2.5 μL, 10×—containing MnCl₂ when required),active kinase (0.001-0.01 Units; 2.5 μL), specific or Poly(Glu4-Tyr)peptide (5-500 μM or 0.01 mg/ml) in kinase buffer and kinase buffer (50μM; 5 μL) are mixed in an eppendorf on ice, A Mg/ATP mix (10 μL; 67.5(or 33.75) mM MgCl₂, 450 (or 225) μM ATP and 1 μCi/μl [γ-³²P]-ATP (3000Ci/mmol)) is added and the reaction is incubated at about 30° C. forabout 10 minutes. The reaction mixture is spotted (20 μL) onto a 2 cm×2cm P81 (phosphocellulose, for positively charged peptide substrates) orWhatman No. 1 (for Poly (Glu4-Tyr) peptide substrate) paper square. Theassay squares are washed 4 times, for 5 minutes each, with 0.75%phosphoric acid and washed once with acetone for 5 minutes. The assaysquares are transferred to a scintillation vial, 5 ml scintillationcocktail are added and ³²P incorporation (cpm) to the peptide substrateis quantified with a Beckman scintillation counter. Percentageinhibition is calculated for each reaction.

Compounds of Formula I, in free form or in pharmaceutically acceptablesalt form, exhibit valuable pharmacological properties, for example, asindicated by the in vitro tests described in this application. Forexample, compounds of Formula I preferably show an IC₅₀ in the range of1×10⁻¹⁰ to 1×10⁵ M, preferably less than 50 nM for wild type BCR-Abl andG250E, E255V, T315I, F317L and M351T BCR-Abl mutants. Compounds ofFormula I preferably, at a concentration of 10 mM, preferably show apercentage inhibition of greater than 50%, preferably greater than about70%, against Abl, Bcr-abl, c-RAF, c-SRC, JNK2α2, lck, MKK6, PDGFRα,SAPK2α, SAPK2β, Tie2 and TrkB kinases. For example:

a).N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzamide(Compound 27) has an IC₅₀ of <0.5 nM, 20 nM, 36 nM, 59 nM <0.5 nM and<0.5 nM for wild type, G250E, E255V, T315I, F317L and M351T Bcr-abl,respectively;b).N-{3-[1-(6-Cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzamide(Compound 25) has an IC50 of 130 nM and 34 nM for the FGFR3 enzyme andcellular assays, respectively, and 149 nM and 2 nM for FLT3 and PDGFRβ,respectively;c).N-{3-[1-(6-Cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzamide(Compound 26) has an IC50 of 65 nM and 37 nM for the FGFR3 enzyme andcellular assays, respectively, and 89 nM and 2 nM for FLT3 and PDGFRβ,respectively;d).N-(4-Methyl-3-{1-[6-(2-morpholin-4-yl-ethylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-3-trifluoromethyl-benzamide(Compound 3), at a concentration of 10 μM, inhibits the followingkinases by the percentage shown in brackets (for example, 100% meanscomplete inhibition, 0% means no inhibition): wild-type Abl (97%), c-RAF(100%), c-SRC (99%), JNK2α2, (97%), lck (100%), MKK6 (100%), PDGFRα(97%), SAPK2α (100%), SAPK2β (100%), Tie2 (99%) and TrkB (97%).

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference for allpurposes.

1. A compound of Formula I:

in which: m and n are independently selected from 0, 1 and 2; R₁ isselected from —XNR₅R₆, —XOR₅, —XC(O)R₅, —XR₅ and —XS(O)₀₋₂R₅; wherein Xis a bond or C₁₋₄alkylene optionally substituted by 1 to 2 C₁₋₆alkylradicals; R₅ is selected from hydrogen, C₁₋₆alkyl, C₁₋₁₀aryl-C₀₋₄alkyl,C₅₋₁₀heteroaryl-C₀₋₄alkyl, C₃₋₁₀cycloalkyl-C₀₋₄alkyl andC₃₋₁₀heterocycloalkyl-C₀₋₄alkyl; and R₆ is selected from hydrogen andC₁₋₆alkyl; or R₅ and R₆ together with the nitrogen to which R₅ and R₆are both attached form heteroaryl or heterocycloalkyl; wherein any aryl,heteroaryl, cycloalkyl and heterocycloalkyl of R₅ or the combination ofR₅ and R₆ can be optionally substituted with 1 to 3 radicalsindependently selected from halo, nitro, cyano, hydroxy, C₁₋₆alkyl,C₁₋₆alkoxy, halo-substituted-alkyl, halo-substituted-alkoxy, —XNR₇R₈,—XOR₇, —XNR₇S(O)₂R₈, —XNR₇S(O)R₈, —XNR₇SR₈, —XC(O)NR₇R₈,—XC(O)NR₇XNR₇R₈, —XNR₇C(O)NR₇R₈, —XNR₇XNR₇R₈, —XNR₇XOR₇,—XNR₇C(═NR₇)NR₇R₈, —XS(O)₂R₉, —XNR₇C(O)R₈, —XNR₇C(O)R₉, —XR₉, —XC(O)OR₈,—XS(O)₂NR₇R₈, —XS(O)NR₇R₈ and —XSNR₇R₈; wherein X is a bond orC₁₋₄alkylene; R₇ and R₈ are independently selected from the groupconsisting of hydrogen and C₁₋₄alkyl; and R₉ is selected fromC₃₋₁₀heterocycloalkyl and C₅₋₁₀heteroaryl; wherein said heterocycloalkylor heteroaryl of R₉ is optionally substituted with a radical selectedfrom the group consisting of C₁₋₄alkyl, —XNR₇XNR₇R₇, XNR₇XOR₇ and —XOR₇;R₂ and R₄ are independently selected from halo, hydroxy, C₁₋₄alkyl,C₁₋₄alkoxy, halo-substituted-C₁₋₄alkyl and halo-substituted-C₁₋₄alkoxy;R₃ is selected from —NR₁₀R₁₁, —NR₁₀C(O)R₁₁, —NR₁₀S(O)₀₋₂R₁₁ and—NR₁₀C(O)NR₁₀R₁₁; wherein R₁₀ is selected from hydrogen and C₁₋₆alkyl;R₁₁ is selected from C₆₋₁₀aryl, C₅₋₁₀heteroaryl, C₃₋₁₀cycloalkyl andC₃₋₁₀heterocycloalkyl; wherein any aryl, heteroaryl, cycloalkyl orheterocycloalkyl of R₁₁ is optionally substituted by 1 to 3 radicalsselected from halo, nitro, cyano, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-alkyl, halo-substituted-alkoxy, —NR₁₂C(O)R₁₃,—NR₁₂C(O)NR₁₂R₁₃, —C(O)NR₁₂R₁₃, —NR₁₂S(O)₀₋₂R₁₃ and —S(O)₀₋₂NR₁₂R₁₃;wherein R₁₂ is selected from hydrogen and C₁₋₆alkyl; R₁₃ is selectedfrom C₆₋₁₀aryl, C₅₋₁₀heteroaryl, C₃₋₁₀cycloalkyl andC₃₋₁₀heterocycloalkyl; wherein any aryl, heteroaryl, cycloalkyl orheterocycloalkyl of R₁₃ is optionally substituted with 1 to 3 radicalsindependently selected from halo, C₁₋₆alkyl, halo-substituted-C₁₋₆alkyl,C₁₋₆alkoxy, halo-substituted-C₁₋₆alkoxy, —XNR₇R₈, C₆₋₁₀aryl-C₀₋₄alkyl,C₅₋₁₀heteroaryl-C₀₋₄alkyl, C₃₋₁₀cycloalkyl-C₀₋₄alkyl,C₃₋₁₀heterocycloalkyl-C₀₋₄alkoxy and C₃₋₁₀heterocycloalkyl-C₀₋₄alkyl;wherein X, R₇ and R₈ are as described above and wherein any aryl,heteroaryl, cycloalkyl or heterocycloalkyl substituent of R₁₃ is furtheroptionally substituted by 1 to 3 radicals independently selected fromhalo, C₁₋₆alkyl, halo-substituted-C₁₋₆alkyl,hydroxy-substituted-C₁₋₆alkyl, C₁₋₆alkoxy, C₃₋₁₀heterocycloalkyl andhalo-substituted-C₁₋₆alkoxy; and the pharmaceutically acceptable saltsand stereoisomers thereof.
 2. The compound of claim 1 of Formula Ia:

in which: p is selected from 0 and 1; n is selected from 0, 1, 2 and 3;q is selected from 0 and 1; R₅ is selected from hydrogen, C₁₋₆alkyl,C₆₋₁₀aryl-C₀₋₄alkyl, C₅₋₁₀heteroaryl-C₀₋₄alkyl,C₃₋₁₀cycloalkyl-C₀₋₄alkyl and C₃₋₁₀heterocycloalkyl-C₀₋₄alkyl; and R₆ isselected from hydrogen and C₁₋₆alkyl; or R₅ and R₆ together with thenitrogen to which R₅ and R₆ are both attached form heteroaryl orheterocycloalkyl; wherein any aryl, heteroaryl, cycloalkyl andheterocycloalkyl of R₅ or the combination of R₅ and R₆ can be optionallysubstituted with 1 to 3 radicals independently selected from halo,nitro, cyano, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, halo-substituted-alkyl,halo-substituted-alkoxy, —XNR₇R₈, —XOR₇, —XNR₇S(O)₂R₈, —XNR₇S(O)R₈,—XNR₇SR₈, —XC(O)NR₇R₈, —XC(O)NR₇XNR₇R₈, —XNR₇C(O)NR₇R₈, —XNR₇XNR₇R₈,—XNR₇XOR₇, —XNR₇C(═NR₇)NR₇R₈, —XS(O)₂R₉, —XNR₇C(O)R₈, —XNR₇C(O)R₉, —XR₉,—XC(O)OR₈, —XS(O)₂NR₇R₈, —XS(O)NR₇R₈ and —XSNR₇R₈; wherein X is a bondor C₁₋₄alkylene; R₇ and R₈ are independently selected from the groupconsisting of hydrogen and C₁₋₄alkyl; and R₉ is selected fromC₃₋₁₀heterocycloalkyl and C₅₋₁₀heteroaryl; wherein said heterocycloalkylor heteroaryl of R₉ is optionally substituted with a radical selectedfrom the group consisting of C₁₋₄alkyl, —XNR₇XNR₇R₇, XNR₇XOR₇ and —XOR₇;wherein X and R₇ are as described above; R₁₀ is selected from hydrogenand C₁₋₆alkyl; R₁₅ is selected from halo, nitro, cyano, hydroxy,C₁₋₆alkyl, C₁₋₆alkoxy, halo-substituted-alkyl andhalo-substituted-alkoxy; and R₁₆ is selected from —NR₁₂C(O)R₁₃,—NR₁₂C(O)NR₁₂R₁₃, —C(O)NR₁₂R₁₃, —NR₁₂S(O)₀₋₂R₁₃ and —S(O)₀₋₂NR₁₂R₁₃;wherein R₁₂ is selected from hydrogen and C₁₋₆alkyl; R₁₃ is selectedfrom C₆₋₁₀aryl, C₅₋₁₀heteroaryl, C₃₋₁₀cycloalkyl andC₃₋₁₀heterocycloalkyl; wherein any aryl, heteroaryl, cycloalkyl orheterocycloalkyl of R₁₃ is optionally substituted with 1 to 3 radicalsindependently selected from halo, C₁₋₆alkyl, halo-substituted-C₁₋₆alkyl,C₁₋₆alkoxy, halo-substituted-C₁₋₆alkoxy, —XNR₇R₈, C₁₋₁₀aryl-C₀₋₄alkyl,C₅₋₁₀heteroaryl-C₀₋₄alkyl, C₃₋₁₀cycloalkyl-C₀₋₄alkyl,C₃₋₁₀heterocycloalkyl-C₀₋₄alkoxy and C₃₋₁₀heterocycloalkyl-C₀₋₄alkyl;wherein X, R₇ and R₈ are as described above and wherein any aryl,heteroaryl, cycloalkyl or heterocycloalkyl substituent of R₁₃ is furtheroptionally substituted by 1 to 3 radicals independently selected fromhalo, C₁₋₆alkyl, halo-substituted-C₁₋₆alkyl,hydroxy-substituted-C₁₋₆alkyl, C₁₋₆alkoxy, C₃₋₁₀heterocycloalkyl andhalo-substituted-C₁₋₆alkoxy.
 3. The compound of claim 2 in which R₅ isselected from hydrogen, morpholino-ethyl, cyclopropyl, methyl,3-(2-oxo-pyrrolidin-1-yl)-propyl, benzo[1,3]dioxol-5-yl,3-(4-methyl-piperazin-1-yl)-propyl, hydroxymethyl-phenyl,(1-hydroxyethyl)-phenyl, morpholino, pyridinyl, methyl-carbonyl,methyl-sulfonyl, methyl-pyridinyl, amino-cyclohexyl, piperidinyl,methyl-piperazinyl-ethyl, dimethyl-pyrazolyl, methyl-pyrazolyl,dimethyl-pyridinyl, methyl-pyridinyl, ethyl-piperazinyl-pyridinyl,amino-carbonyl-pyridinyl, cyano-pyridinyl, dimethyl-amino-ethyl,methoxy-ethyl, methyl-pyrrolidinyl-ethyl, ethyl-pyrazolyl,dimethyl-amino-propyl, isopropyl, furanyl-methyl,methyl-piperazinyl-propyl, benzo[1,3]dioxol-5-ylmethyl,2-methyl-6-morpholin-4-yl-pyridin-3-yl, methyl-pyrimidinyl,methoxy-pyridinyl, fluoro-phenyl, dimethyl-amino-ethyl-aminocarbonyl,pyridinyl-methyl, thiazolyl-methyl, methyl-pyrazinyl-methyl,imidazolyl-propyl, amino-carbonyl-phenyl, or R₅ and R₆ together with thenitrogen atom to which they are both attached form a group selected frommorpholino, piperidinyl and piperazinyl optionally substituted with agroup selected from ethyl, pyridinyl and morpholino.
 4. The compound ofclaim 3 in which R₁₆ is selected from —NHC(O)R₁₃, —NHC(O)NHR₁₃,—C(O)NHR₁₃, —NHS(O)₂R₁₃ and —S(O)₂NHR₁₃; wherein R₁₃ is selected fromphenyl, pyridazinyl, pyridinyl, furanyl, pyrrolyl, imidazolyl,pyrazolyl, quinoxalinyl, thienyl and thiazolyl; wherein R₁₃ isoptionally substituted with 1 to 3 radicals independently selected frommethyl, t-butyl, halo, trifluoromethyl, diethyl-amino, dimethyl-amino,benzyl, piperidinyl-amino, pyrrolidinyl-methoxy,ethyl-piperazinyl-methyl, morpholino, methyl-piperazinyl,methyl-piperazinyl-methyl, ethyl-piperazinyl, methyl-imidazolyl,morpholino-methyl, pyrrolidinyl-piperidinyl, piperazinyl-methyl,hydroxy-piperidinyl, 1-methyl-piperidin-4-yloxy, piperidinyl-oxy,methyl-pyrazinyl, pyrazinyl and hydroxyethyl-piperazinyl.
 5. Thecompound of claim 1 selected fromN-[4-methyl-3-(1-{6-[4-(2-morpholin-4-yl-ethyl)-phenylamino]-pyrimidin-4-yl}-1H-imidazol-2-ylamino)-phenyl]-3-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-(4-ethyl-piperazin-1-yl)-5-trifluoromethyl-benzamide,N-(4-methyl-3-{1-[6-(2-morpholin-4-yl-ethylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-3-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-trifluoromethyl-benzamide,N-{4-methyl-3-[1-(6-methylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-phenyl}-3-trifluoromethyl-benzamide,N-[4-methyl-3-(1-{6-[3-(2-oxo-pyrrolidin-1-yl)-propylamino]-pyrimidin-4-yl}-1H-imidazol-2-ylamino)-phenyl]-3-trifluoromethyl-benzamide,N-(3-{1-[6-(benzo[1,3]dioxol-5-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-4-methyl-phenyl)-3-trifluoromethyl-benzamide,N-[4-methyl-3-(1-{6-[3-(4-methyl-piperazin-1-yl)-propylamino]-pyrimidin-4-yl}-1H-imidazol-2-ylamino)-phenyl]-3-trifluoromethyl-benzamide,{6-[2-(2-chloro-phenylamino)-imidazol-1-yl]-pyrimidin-4-yl}-cyclopropyl-amine,(3-{6-[2-(2-chloro-phenylamino)-imidazol-1-yl]-pyrimidin-4-ylamino}-phenyl)-methanol,1-(3-{6-[2-(2-chloro-phenylamino)-imidazol-1-yl]-pyrimidin-4-ylamino}-phenyl)-ethanol,{6-[2-(2-chloro-phenylamino)-imidazol-1-yl]-pyrimidin-4-yl}-[4-(2-morpholin-4-yl-ethyl)-phenyl]-amine,{6-[2-(2-chloro-phenylamino)-imidazol-1-yl]-pyrimidin-4-yl}-(4-morpholin-4-yl-phenyl)-amine,N-(3-{6-[2-(2-chloro-phenylamino)-imidazol-1-yl]-pyrimidin-4-ylamino}-phenyl)-acetamide,1-(3-{6-[2-(2-chloro-phenylamino)-imidazol-1-yl]-pyrimidin-4-ylamino}-propyl)-pyrrolidin-2-one,benzo[1,3]dioxol-5-yl-{6-[2-(2-chloro-phenylamino)-imidazol-1-yl]-pyrimidin-4-yl}-amine,{6-[2-(2-chloro-phenylamino)-imidazol-1-yl]-pyrimidin-4-yl}-pyridin-3-yl-amine,N-(4-methyl-3-{1-[6-(pyridin-3-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-3-trifluoromethyl-benzamide,{6-[2-(2-chloro-phenylamino)-imidazol-1-yl]-pyrimidin-4-yl}-(6-methyl-pyridin-3-yl)-amine,N-(4-methyl-3-{1-[6-(6-methyl-pyridin-3-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-3-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-morpholin-4-yl-5-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-(4-methyl-piperazin-1-yl)-5-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-(4-ethyl-piperazin-1-yl)-5-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-4-morpholin-4-yl-3-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzamide,3-(4-methyl-imidazol-1-yl)-N-{4-methyl-3-[1-(6-methylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-phenyl}-5-trifluoromethyl-benzamide,N-{4-methyl-3-[1-(6-methylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-phenyl}-4-morpholin-4-yl-3-trifluoromethyl-benzamide,3-(4-ethyl-piperazin-1-yl)-N-{4-methyl-3-[1-(6-methylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-phenyl}-5-trifluoromethyl-benzamide,N-{4-methyl-3-[1-(6-methylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-phenyl}-3-(4-methyl-piperazin-1-yl)-5-trifluoromethyl-benzamide,N-{3-[1-(6-methylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-phenyl}-4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzamide,3-(4-ethyl-piperazin-1-ylmethyl)-N-{4-methyl-3-[1-(6-methylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-phenyl}-5-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-4-morpholin-4-ylmethyl-3-trifluoromethyl-benzamide,N-{4-methyl-3-[1-(6-methylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-phenyl}-4-morpholin-4-ylmethyl-3-trifluoromethyl-benzamide,N-{3-[1-(6-amino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzamide,N-{3-[1-(6-amino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzamide,N-{3-[1-(6-amino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-phenyl}-3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzamide,N-{3-[1-(6-amino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-4-morpholin-4-yl-3-trifluoromethyl-benzamide,N-{3-[1-(6-amino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-(4-ethyl-piperazin-1-yl)-5-trifluoromethyl-benzamide,N-{3-[1-(6-amino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-(4-methyl-piperazin-1-yl)-5-trifluoromethyl-benzamide,N-{3-[1-(6-amino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-morpholin-4-ylmethyl-5-trifluoromethyl-benzamide,3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-5-methoxy-N-[4-(2-methyl-imidazol-1-yl)-3-trifluoromethyl-phenyl]-benzamide,N-{3-[1-(6-acetylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-trifluoromethyl-benzamide,N-{3-[1-(6-methanesulfonylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-trifluoromethyl-benzamide,N-{3-[1-(2-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-trifluoromethyl-benzamide,3-[1-(2-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-N-[4-(2-methyl-imidazol-1-yl)-3-trifluoromethyl-phenyl]-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-piperazin-1-ylmethyl-5-trifluoromethyl-benzamide,N-{3-[1-(6-amino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-piperazin-1-ylmethyl-5-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-5-methoxy-phenyl}-4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-5-methoxy-phenyl}-3-(4-ethyl-piperazin-1-ylmethyl)-5-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-(piperidin-4-yloxy)-5-trifluoromethyl-benzamide,N-{3-[1-(6-amino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-(piperidin-4-yloxy)-5-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-5-methoxy-phenyl}-3-(4-pyrrolidin-1-yl-piperidin-1-yl)-5-trifluoromethyl-benzamide,1-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-[4-(2-methyl-imidazol-1-yl)-3-trifluoromethyl-phenyl]-urea,1-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-[4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-urea,pyridazine-4-carboxylic acid{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-amide,2-chloro-N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-isonicotinamide,furan-2-carboxylic acid{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-amide,1-methyl-1H-pyrrole-2-carboxylic acid{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-amide,1H-imidazole-2-carboxylic acid{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-amide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-4-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-6-methyl-nicotinamide,1-tert-butyl-5-methyl-1H-pyrazole-3-carboxylic acid{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-amide,N-[4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-4-methyl-3-{1-[6-(2-morpholin-4-yl-ethylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-benzamide,3-(4-methyl-imidazol-1-yl)-N-(4-methyl-3-{1-[6-(2-morpholin-4-yl-ethylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-5-trifluoromethyl-benzamide,4-methyl-N-[4-(2-methyl-imidazol-1-yl)-3-trifluoromethyl-phenyl]-3-{1-[6-(2-morpholin-4-yl-ethylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-benzamide,N-(4-methyl-3-{1-[6-(2-morpholin-4-yl-ethylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-3-(1-methyl-piperidin-4-yloxy)-5-trifluoromethyl-benzamide,pyrazine-2-carboxylic acid{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-amide,5-methyl-pyrazine-2-carboxylic acid{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-amide,quinoxaline-6-carboxylic acid{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-amide,5-tert-butyl-2-methyl-4-morpholin-4-ylmethyl-furan-3-carboxylic acid{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-amide,5-tert-butyl-2-methyl-2H-pyrazole-3-carboxylic acid{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-amide,2-benzyl-5-tert-butyl-2H-pyrazole-3-carboxylic acid{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-amide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-(piperidin-4-ylamino)-5-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-(pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-benzamide,5-tert-butyl-2-methyl-furan-3-carboxylic acid{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-amide,5-tert-butyl-3-methyl-furan-2-carboxylic acid{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-amide,5-tert-butyl-2-diethylamino-furan-3-carboxylic acid{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-amide,5-tert-butyl-4-diethylamino-2-methyl-furan-3-carboxylic acid{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-amide,5-tert-butyl-thiophene-2-carboxylic acid{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-amide,5-tert-butyl-3-methyl-furan-2-carboxylic acid(4-methyl-3-{1-[6-(2-morpholin-4-yl-ethylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-amide,5-tert-butyl-thiophene-2-carboxylic acid(4-methyl-3-{1-[6-(2-morpholin-4-yl-ethylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-amide,5-tert-butyl-2-methyl-furan-3-carboxylic acid(4-methyl-3-{1-[6-(2-morpholin-4-yl-ethylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-amide,N-(3-{1-[6-(4-amino-cyclohexylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-4-methyl-phenyl)-3-trifluoromethyl-benzamide,N-(4-methyl-3-{1-[6-(piperidin-4-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-3-trifluoromethyl-benzamide,N-[4-methyl-3-(1-{6-[2-(4-methyl-piperazin-1-yl)-ethylamino]-pyrimidin-4-yl}-1H-imidazol-2-ylamino)-phenyl]-3-trifluoromethyl-benzamide,N-(3-{1-[6-(2,5-dimethyl-2H-pyrazol-3-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-4-methyl-phenyl)-3-trifluoromethyl-benzamide,N-(4-methyl-3-{1-[6-(4-methyl-piperazin-1-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-3-trifluoromethyl-benzamide,N-(4-methyl-3-{1-[6-(2-methyl-2H-pyrazol-3-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-3-trifluoromethyl-benzamide,N-(3-{1-[6-(2,6-dimethyl-pyridin-3-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-4-methyl-phenyl)-3-trifluoromethyl-benzamide,N-(4-methyl-3-{1-[6-(2-methyl-pyridin-3-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-3-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-(4-methyl-piperazin-1-yl)-5-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-5-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-piperazin-1-yl-5-trifluoromethyl-benzamide,N-{4-chloro-3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-phenyl}-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-fluoro-phenyl}-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-2-methyl-phenyl}-benzamide,N-{5-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-2-fluoro-phenyl}-benzamide,N-{5-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-2-methyl-phenyl}-benzamide,N-{4-chloro-3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-phenyl}-4-morpholin-4-ylmethyl-3-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-fluoro-phenyl}-4-morpholin-4-ylmethyl-3-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-2-methyl-phenyl}-4-morpholin-4-ylmethyl-3-trifluoromethyl-benzamide,N-{4-chloro-3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-phenyl}-3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-fluoro-phenyl}-3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-2-methyl-phenyl}-3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzamide,N-{5-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-2-fluoro-phenyl}-3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzamide,N-{5-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-2-methyl-phenyl}-3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methoxy-phenyl}-benzamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-trifluoromethyl-benzenesulfonamide,3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-N-(3-trifluoromethyl-phenyl)-benzenesulfonamide,N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-fluoro-phenyl}-3-dimethylamino-5-trifluoromethyl-benzamide,N-{5-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-2-methyl-phenyl}-3-dimethylamino-5-trifluoromethyl-benzamide,N-{4-chloro-3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-phenyl}-3-dimethylamino-5-trifluoromethyl-benzamide,3-(4-methyl-imidazol-1-yl)-N-(4-methyl-3-{1-[6-(pyridin-2-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-5-trifluoromethyl-benzamide,4-(4-ethyl-piperazin-1-ylmethyl)-N-(4-methyl-3-{1-[6-(pyridin-2-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-3-trifluoromethyl-benzamide,3-(4-ethyl-piperazin-1-yl)-N-(4-methyl-3-{1-[6-(pyridin-2-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-5-trifluoromethyl-benzamide,4-chloro-N-(4-methyl-3-{1-[6-(pyridin-2-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-3-trifluoromethyl-benzamide,N-[3-(1-{6-[5-(4-ethyl-piperazin-1-yl)-pyridin-2-ylamino]-pyrimidin-4-yl}-1H-imidazol-2-ylamino)-4-methyl-phenyl]-3-trifluoromethyl-benzamide,N-(4-methyl-3-{1-[6-(4-methyl-pyridin-2-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-3-trifluoromethyl-benzamide,N-(3-{1-[6-(4,6-dimethyl-pyridin-2-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-4-methyl-phenyl)-3-trifluoromethyl-benzamide,6-(6-{2-[2-methyl-5-(3-trifluoromethyl-benzoylamino)-phenylamino]-imidazol-1-yl}-pyrimidin-4-ylamino)-nicotinamide,N-(4-methyl-3-{1-[6-(5-methyl-pyridin-2-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-3-trifluoromethyl-benzamide,N-(3-{1-[6-(5-cyano-pyridin-2-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-4-methyl-phenyl)-3-trifluoromethyl-benzamide,4-chloro-N-{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-trifluoromethyl-benzamide,4-chloro-N-(4-methyl-3-{1-[6-(2-morpholin-4-yl-ethylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-3-trifluoromethyl-benzamide,5-tert-butyl-2-methyl-2H-pyrazole-3-carboxylic acid(4-methyl-3-{1-[6-(2-morpholin-4-yl-ethylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-amide,N-(3-{1-[6-(2-dimethylamino-ethylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-4-methyl-phenyl)-3-trifluoromethyl-benzamide,N-(4-methyl-3-{1-[6-(3-morpholin-4-yl-propylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-3-trifluoromethyl-benzamide,N-(3-{1-[6-(2-methoxy-ethylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-4-methyl-phenyl)-3-trifluoromethyl-benzamide,N-[4-methyl-3-(1-{6-[2-(1-methyl-pyrrolidin-2-yl)-ethylamino]-pyrimidin-4-yl}-1H-imidazol-2-ylamino)-phenyl]-3-trifluoromethyl-benzamide,N-(4-methyl-3-{1-[6-(pyridin-2-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-3-trifluoromethyl-benzamide,N-[4-methyl-3-(1-pyrimidin-4-yl-1H-imidazol-2-ylamino)-phenyl]-3-trifluoromethyl-benzamide,N-[4-methyl-3-(1-pyrimidin-2-yl-1H-imidazol-2-ylamino)-phenyl]-3-trifluoromethyl-benzamide,N-{4-methyl-3-[1-(4-methylamino-pyrimidin-2-yl)-1H-imidazol-2-ylamino]-phenyl}-3-trifluoromethyl-benzamide,N-{4-methyl-3-[1-(2-methylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-phenyl}-3-trifluoromethyl-benzamide,N-(4-methyl-3-{1-[4-(2-morpholin-4-yl-ethylamino)-pyrimidin-2-yl]-1H-imidazol-2-ylamino}-phenyl)-3-trifluoromethyl-benzamide,N-(4-methyl-3-{1-[2-(2-morpholin-4-yl-ethylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-3-trifluoromethyl-benzamide,N-(3-{1-[6-(2-ethyl-2H-pyrazol-3-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-4-methyl-phenyl)-3-trifluoromethyl-benzamide,N-(3-{1-[6-(3-dimethylamino-propylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-4-methyl-phenyl)-3-trifluoromethyl-benzamide,N-{3-[1-(6-isopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-trifluoromethyl-benzamide,N-[3-(1-{6-[(furan-3-ylmethyl)-amino]-pyrimidin-4-yl}-1H-imidazol-2-ylamino)-4-methyl-phenyl]-3-trifluoromethyl-benzamide,N-[4-methyl-3-(1-{6-[3-(4-methyl-piperazin-1-yl)-propylamino]-pyrimidin-4-yl}-1H-imidazol-2-ylamino)-phenyl]-3-trifluoromethyl-benzamide,N-[3-(1-{6-[(benzo[1,3]dioxol-5-ylmethyl)-amino]-pyrimidin-4-yl}-1H-imidazol-2-ylamino)-4-methyl-phenyl]-3-trifluoromethyl-benzamide,N-(4-methyl-3-{1-[6-(2-methyl-6-morpholin-4-yl-pyridin-3-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-3-trifluoromethyl-benzamide,N-(4-methyl-3-{1-[6-(4-methyl-pyrimidin-2-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-3-trifluoromethyl-benzamide,N-(3-{1-[6-(6-methoxy-pyridin-3-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-4-methyl-phenyl)-3-trifluoromethyl-benzamide,N-{4-methyl-3-[1-(6-morpholin-4-yl-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-phenyl}-3-trifluoromethyl-benzamide,N-(3-{1-[6-(4-ethyl-piperazin-1-yl)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-4-methyl-phenyl)-3-trifluoromethyl-benzamide,N-(3-{1-[6-(3-fluoro-phenylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-4-methyl-phenyl)-3-trifluoromethyl-benzamide,N-(3-{1-[6-(3-dimethylamino-ethyl-formamide-phenylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-4-methyl-phenyl)-3-trifluoromethyl-benzamide,N-[4-methyl-3-(1-{6-[(pyridin-3-ylmethyl)-amino]-pyrimidin-4-yl}-1H-imidazol-2-ylamino)-phenyl]-3-trifluoromethyl-benzamide,N-[4-methyl-3-(1-{6-[(pyridin-4-ylmethyl)-amino]-pyrimidin-4-yl}-1H-imidazol-2-ylamino)-phenyl]-3-trifluoromethyl-benzamide,N-(4-methyl-3-{1-[6-(4-morpholin-4-yl-piperidin-1-yl)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-3-trifluoromethyl-benzamide,N-[4-methyl-3-(1-{6-[(thiazol-2-ylmethyl)-amino]-pyrimidin-4-yl}-1H-imidazol-2-ylamino)-phenyl]-3-trifluoromethyl-benzamide,N-[4-methyl-3-(1-{6-[(pyridin-2-ylmethyl)-amino]-pyrimidin-4-yl}-1H-imidazol-2-ylamino)-phenyl]-3-trifluoromethyl-benzamide,N-[4-methyl-3-(1-{6-[(6-methyl-pyrazin-2-ylmethyl)-amino]-pyrimidin-4-yl}-1H-imidazol-2-ylamino)-phenyl]-3-trifluoromethyl-benzamide,N-(4-methyl-3-{1-[6-(4-pyridin-2-yl-piperazin-1-yl)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-3-trifluoromethyl-benzamide,N-(3-{1-[6-(3-imidazol-1-yl-propylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-4-methyl-phenyl)-3-trifluoromethyl-benzamide,N-(4-methyl-3-{1-[6-(pyrazin-2-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-3-trifluoromethyl-benzamide,N-(3-{1-[6-(3-formamide-phenylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-4-methyl-phenyl)-3-trifluoromethyl-benzamide,4-methyl-3-{1-[6-(2-morpholin-4-yl-ethylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-N-(3-trifluoromethyl-phenyl)-benzamide,4-methyl-3-{1-[6-(4-methyl-piperazin-1-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-N-(3-trifluoromethyl-phenyl)-benzamide,N-(4-chloro-3-trifluoromethyl-phenyl)-4-methyl-3-{1-[6-(2-morpholin-4-yl-ethylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-benzamide,N-(4-chloro-3-trifluoromethyl-phenyl)-4-methyl-3-{1-[6-(4-methyl-piperazin-1-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-benzamide,1-tert-butyl-5-(4-methyl-piperazin-1-ylmethyl)-1H-pyrazole-3-carboxylicacid{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-amide,1-tert butyl-5-morpholin-4-ylmethyl-1H-pyrazole-3-carboxylic acid{3-[1-(6-cyclopropylamino-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-amide,N-(4-tert-butyl-thiazol-2-yl)-4-methyl-3-{1-[6-(2-morpholin-4-yl-ethylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-benzamide,N-(4-tert-butyl-thiazol-2-yl)-4-methyl-3-{1-[6-(4-methyl-piperazin-1-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-benzamide,N-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-4-methyl-3-{1-[6-(4-methyl-piperazin-1-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-benzamide,N-(4-methyl-3-{1-[6-(4-methyl-piperazin-1-ylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-benzamide,N-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-4-methyl-3-{1-[6-(2-morpholin-4-yl-ethylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-benzamide,N-(4-methyl-3-{1-[2-(2-morpholin-4-yl-ethylamino)-pyridin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-3-trifluoromethyl-benzamide,N-{3-[1-(4-acetylamino-pyridin-2-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-3-trifluoromethyl-benzamideand2-{2-[2-Methyl-5-(3-trifluoromethyl-benzoylamino)-phenylamino]-imidazol-1-yl}-isonicotinamide.6. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of claim 1 in combination with a pharmaceuticallyacceptable excipient.
 7. A method for treating leukemia in an animal inwhich inhibition of kinase activity can inhibit or ameliorate thepathology and/or symptomology of the kinase mediated disease, whichmethod comprises administering to the animal a therapeutically effectiveamount of a compound of claim
 1. 8. The method of claim 7 in which thekinase is selected from the group consisting of Abl, BCR-Abl, PDGF-R,trkB, c-SRC, BMX, FGFR3, b-RAF, SGK, Tie2, Lck, JNK2α2, MKK4, c-RAF,MKK6, SAPK2α and SAPK2β.